Heterocyclic compound

ABSTRACT

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity.A compound represented by the formula (I):wherein each symbol is as described in the description, or a salt thereof has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound, particularly,a heterocyclic compound having an orexin type 2 receptor agonistactivity.

BACKGROUND OF THE INVENTION

Orexin is a neuropeptide specifically produced in particular neuronslocated sparsely in the lateral hypothalamus and its surrounding area,and consists of two subtypes, orexin A and orexin B. Both orexin A andorexin B are endogenous is ligands of the orexin receptors, which are Gprotein-coupled receptors mainly present in the brain, and two types ofsubtypes, type 1 and type 2, are known for the orexin receptors(non-patent document 1).

Since orexin-producing neurons (orexin neurons) are localized in thevicinity of the feeding center, and intraventricular administration oforexin peptide results in an increase in food intake, orexin initiallyattracted attention as a neuropeptide having a feeding behavioralregulation. Thereafter, however, it was reported that the cause of dognarcolepsy is genetic variation of orexin type 2 receptor (non-patentdocument 2), and the role of orexin in controlling sleep and wakefulnesshas been also attracted.

From the studies using a transgenic mouse having denatured orexinneurons and a double transgenic mouse obtained by crossing this mousewith orexin overexpressing transgenic mouse, it was clarified thatnarcolepsy-like symptoms that appear by degeneration of orexin neuronsdisappear due to sustained expression of orexin. Similarly, when orexinpeptide was intraventricularly administered to a transgenic mouse havingdenatured orexin neuron, improvement of narcolepsy-like symptoms wasalso observed (non-patent document 3). Studies of orexin type 2 receptorknockout mice have suggested that orexin type 2 receptor is importantfor maintaining arousal (non-patent document 4, non-patent document 5).Such background suggests that orexin type 2 receptor agonists becometherapeutic drugs for narcolepsy or therapeutic drugs for other sleepdisorders exhibiting excessive sleepiness (non-patent document 6).

In addition, it is suggested that a peptidic agonist that selectivelyacts on the orexin type 2 receptor improves obesity due to high fat dietload in mice (non-patent document 7).

In addition, it is suggested that intraventricular administration oforexin peptide shortens the systemic anesthetic time of rat (non-patentdocument 8).

In addition, it is suggested that patients with sleep apnea syndromeshow low orexin A concentration levels in plasma (non-patent document9).

In addition, it is suggested that intraventricular administration oforexin peptide improves memory retention of senescence-accelerated modelmouse (SAMP8) with cognitive dysfunction (non-patent document 10).

In addition, it is suggested that Orexin type 2 receptor agonist will bea therapeutic drug for cardiac failure (patent document 1, non-patentdocument 11).

In addition, it is suggested that the daytime sleepiness of Parkinson'sdisease patients is caused by orexin nerve fallout (non-patent document12).

In addition, it is suggested that orexin regulates bone formation andbone loss, and orexin type 2 receptor agonist will be a therapeutic drugfor diseases related to bone loss such as osteoporosis, rheumatoidarthritis and the like (patent document 2).

In addition, it is suggested that orexin receptor agonist is useful forthe prophylaxis or treatment of sepsis, severe sepsis and septic shock,since the mortality was significantly improved by mere continuousadministration of orexin from the periphery in septic shock model mouse(patent document 3).

Therefore, a compound having an orexin type 2 receptor agonist activityis expected to be useful as a novel therapeutic drug for narcolepsy,idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbanceof consciousness such as coma and the like, narcolepsy syndromeaccompanied by narcolepsy-like symptoms, hypersomnia syndromeaccompanied by daytime hypersomnia (e.g., Parkinson's disease,Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer, obesity,insulin resistance syndrome, cardiac failure, diseases related to boneloss, sepsis and the like, further, anesthetic antagonist, aprophylactic or therapeutic drug for side effects and complications dueto anesthesia.

As sulfonamide derivatives, a compound represented by the formula

wherein each symbol is as described in the document (Patent Document 4)has been reported.

In addition, as compounds having an orexin type 2 receptor agonistactivity, the following compounds have been reported.

A compound represented by the formula

wherein each symbol is as described in the document (Patent Document 5).

A compound represented by the formula

wherein each symbol is as described in the document (Patent Document 6).

A compound represented by the formula

wherein each symbol is as described in the document (Patent Document 7).

A compound represented by the formula

wherein each symbol is as described in the document (Patent Document 8).

A compound represented by the formula

wherein each symbol is as described in the document (Patent Document 9).

However, it is considered that these compounds are not satisfactory interms of activity, pharmacokinetics or safety, and therefore,development of a compound having an orexin type 2 receptor agonistactivity is still desired.

DOCUMENT LIST Patent Document

-   Patent Document 1: WO 2015/073707 A1-   Patent Document 2: WO 2015/048091 A1-   Patent Document 3: WO 2015/147240 A1-   Patent Document 4: WO 2012/137982 A9-   Patent Document 5: WO 2017/135306 A1-   Patent Document 6: WO 2018/164191 A1-   Patent Document 7: WO 2018/164192 A1-   Patent Document 8: WO 2019/027003 A1-   Patent Document 9: WO 2019/027058 A1

Non-Patent Document

-   Non-Patent Document 1: Cell, Vol.92, 573-585, 1998-   Non-Patent Document 2: Cell, Vol.98, 365-376, 1999-   Non-Patent Document 3: Proc. Natl. Acad. Sci. USA, Vol.101,    4649-4654, 2004-   Non-Patent Document 4: Cell, Vol.98, 437-451, 1999-   Non-Patent Document 5: Neuron, Vol.38, 715-730, 2003-   Non-Patent Document 6: CNS Drugs, Vol.27, 83-90, 2013-   Non-Patent Document 7: Cell Metabolism, Vol.9, 64-76, 2009-   Non-Patent Document 8: Neuroscience, Vol.121, 855-863, 2003-   Non-Patent Document 9: Respiration, Vol.71, 575-579, 2004-   Non-Patent Document 10: Peptides, Vol.23, 1683-1688, 2002-   Non-Patent Document 11: Journal of the American College of    Cardiology. Vol. 66, 2015, Pages 2522-2533-   [Non-Patent Document 12: Brain. Vol. 130, 2007, Pages 1586-1595

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide a heterocyclic compound having anorexin type 2 receptor agonist activity.

Means of Solving the Problems

The present inventors have found that a compound represented by thefollowing formula (I) or a salt thereof (sometimes to be referred to ascompound (I) in the present specification) has an orexin type 2 receptoragonist activity. As a result of further studies, they have completedthe present invention.

Accordingly, the present invention relates to the followings.

-   [1] A compound represented by the formula:

-   wherein-   R¹ is an optionally substituted C₁₋₆ alkylsulfonyl group, an    optionally substituted mono- or di-C₁₋₆ alkylaminosulfonyl group, an    optionally substituted 3- to 6-membered cyclylsulfonyl group, a    formylcarbonyl group, a carboxycarbonyl group, a carbamoylcarbonyl    group, an optionally substituted C₁₋₆ alkyl-carbonyl group, an    optionally substituted C₁₋₆ alkoxy-carbonyl group, an optionally    substituted mono- or di-C₁₋₆ alkyl-carbamoyl group, an optionally    substituted C₁₋₆ alkyl-carbonyl-carbonyl group, an optionally    substituted C₁₋₆ alkoxy-carbonyl-carbonyl group, an optionally    substituted mono- or di-C₁₋₆ alkyl-carbamoyl-carbonyl group or an    optionally substituted 3- to 6-membered cyclylcarbonyl group;-   R² and R³ are each independently a hydrogen atom, an optionally    substituted C₁₋₆ alkyl group or a halogen atom;-   X is an optionally substituted methylene group, NR^(a) or an oxygen    atom;-   R^(a) is a hydrogen atom or an optionally substituted C₁₋₆ alkyl    group;-   Y and Z are each independently a carbon atom, CH or a nitrogen atom;

-   is Z—Y or Z═Y;-   Ring A is an optionally further substituted 5- or 6-membered    nitrogen-containing non-aromatic heterocycle;-   L is an optionally substituted methylene group, an oxygen atom,    —O-L¹-, -L¹-O— or -L¹-L²-;-   L¹ and L² are each independently an optionally substituted methylene    group; and-   Ring B is an optionally further substituted 4- to 7-membered ring,-   or a salt thereof.-   [2] The compound or salt according to the above-mentioned [1],    wherein L is an optionally substituted methylene group or an oxygen    atom.-   [3] The compound or salt according to the above-mentioned [1],    wherein-   R¹ is-   (1) an optionally halogenated C₁₋₆ alkylsulfonyl group,-   (2) a C₃₋₆ cycloalkylsulfonyl group optionally substituted by 1 25    to 3 halogen atoms,-   (3) a mono- or di-C₁₋₆ alkyl-carbamoyl-carbonyl group,-   (4) a C₃₋₆ cycloalkyl-carbonyl group optionally substituted by 1 to    3 C₁₋₆ alkoxy groups, or-   (5) a 3- to 6-membered non-aromatic heterocyclylcarbonyl group;-   R² is a hydrogen atom or a halogen atom;-   R³ is a hydrogen atom or a halogen atom;-   X is-   (1) a methylene group optionally substituted by 1 or 2 substituents    selected from a C₁₋₆ alkoxy group and a halogen atom, or-   (2) a carbonyl group;-   the partial structure represented by

is a partial structure represented by

-   Ring A is a 5- or 6-membered nitrogen-containing non-aromatic    heterocycle optionally further substituted by 1 to 3 substituents    selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionally        deuterated) optionally substituted by 1 to 3 substituents        selected from        -   (i) a halogen atom,        -   (ii) a hydroxy group, and        -   (iii) a C₃₋₁₀ cycloalkyl group,    -   (d) a C₁₋₆ alkoxy group,    -   (e) a C₃₋₁₀ cycloalkyl group,    -   (f) a C₁₋₆ alkoxy-carbonyl group, and    -   (g) a mono- or di-C₁₋₆ alkylamino group, and having one oxo        group on the carbon atom adjacent to Z;-   L is a methylene group; and-   Ring B is a 4- to 7-membered ring further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group,    -   (c) a C₃₋₁₀ cycloalkyl group,    -   (d) a C₆₋₁₄ aryl group (the C₆₋₁₄ aryl group is optionally fused        with a 3- to 8-membered monocyclic non-aromatic heterocycle)        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom,        -   (ii) an optionally halogenated C₁₋₆ alkyl group, and        -   (iii) a C₁₋₆ alkoxy group,    -   (e) a 5- to 14-membered aromatic heterocyclic group optionally        substituted by 1 to 3 C₁₋₆ alkyl groups,    -   (f) a 3- to 14-membered non-aromatic heterocyclic group        optionally substituted by 1 to 3 substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group,    -   (g) a C₆₋₁₄ aryloxy group,    -   (h) a C₇₋₁₆ aralkyloxy group, and    -   (i) a C₂₋₆ alkenyl group.-   [4] The compound or salt according to the above-mentioned [1],    wherein-   R¹ is-   (1) a C₁₋₆ alkylsulfonyl group, or-   (2) a C₃₋₆ cycloalkylsulfonyl group optionally substituted by 1 to 3    halogen atoms;-   R² is a hydrogen atom;-   R³ is a hydrogen atom;-   X is a methylene group;-   the partial structure represented by

is a partial structure represented by

-   Ring A is-   (1) a dihydropyridine ring optionally substituted by 1 to 3 C₁₋₆    alkyl groups, and having one oxo group on the carbon atom adjacent    to Z, or-   (2) a dihydropyrimidine ring optionally substituted by 1 to 3 C₁₋₆    alkyl groups, and having one oxo group on the carbon atom adjacent    to Z;-   L is a methylene group; and-   Ring B is-   (1) a benzene ring further substituted by 1 or 2 substituents    selected from    -   (a) a halogen atom, and    -   (b) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 halogen        atoms, or-   (2) a thiazole ring further substituted by C₆₋₁₄ aryl group(s)    optionally substituted by 1 to 3 halogen atoms.-   [5] The compound or salt according to the above-mentioned [1],    wherein-   R¹ is a C₃₋₆ cycloalkylsulfonyl group optionally substituted by one    halogen atom;-   R² is a hydrogen atom;-   R³ is a hydrogen atom;-   X is a methylene group;-   the partial structure represented by

is a partial structure represented by

-   Ring A is a dihydropyrimidine ring substituted by one C₁₋₆ alkyl    group, and having one oxo group on the carbon atom adjacent to Z;-   L is a methylene group; and-   Ring B is a benzene ring further substituted by    -   (a) a halogen atom, and    -   (b) a phenyl group optionally substituted by 1 to 3 halogen        atoms.-   [6]    N-[(5R,6S)-5-[(2-Fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropanesulfonamide    or a salt thereof.-   [7]    1-Fluoro-N-[(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamide    or a salt thereof.-   [8]    N-{(5R,6S)-4-Oxo-3-(propan-2-yl)-5-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin-6-yl}cyclopropanesulfonamide    or a salt thereof.-   [9] A medicament comprising the compound or salt according to the    above-mentioned [1].-   [10] The medicament according to the above-mentioned [9], which is    an orexin type 2 receptor agonist.-   [11] The medicament according to the above-mentioned [9], which is    an agent for the prophylaxis or treatment of narcolepsy.-   [12] The compound or salt according to the above-mentioned [1] for    use in the prophylaxis or treatment of narcolepsy.-   [13] A method for activating an orexin type 2 receptor in a mammal,    which comprises administering an effective amount of the compound or    salt according to the above-mentioned [1] to the mammal.-   [14] A method for preventing or treating narcolepsy in a mammal,    which comprises administering an effective amount of the compound or    salt according to the above-mentioned [1] to the mammal.-   [15] Use of the compound or salt according to the above-mentioned    [1] for the manufacture of an agent for the prophylaxis or treatment    of narcolepsy.

Effect of the Invention

The compound of the present invention has an orexin type 2 receptoragonist activity, and is useful as an agent for the prophylaxis ortreatment of narcolepsy.

(DETAILED DESCRIPTION OF THE INVENTION)

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, is isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or alkyl-carbamoylgroup” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following Substituent Group A.

[Substituent Group A]

-   (1) a halogen atom,-   (2) a nitro group,-   (3) a cyano group,-   (4) an oxo group,-   (5) a hydroxy group,-   (6) an optionally halogenated C₁₋₆ alkoxy group,-   (7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),-   (8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),-   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,    pyridyloxy),-   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,    morpholinyloxy, piperidinyloxy),-   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),-   (12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy,    1-naphthoyloxy, 2-naphthoyloxy),-   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,    ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),-   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,    methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,    diethylcarbamoyloxy),-   (15) a C₆₋₁₄ aryl-carbanoyloxy group (e.g., phenylcarbamoyloxy,    naphthylcarbamoyloxy),-   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group    (e.g., nicotinoyloxy),-   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group    (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),-   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,    methylsulfonyloxy, trifluoromethylsulfonyloxy),-   (19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆    alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),-   (20) an optionally halogenated C₁₋₆ alkylthio group,-   (21) a 5- to 14-membered aromatic heterocyclic group,-   (22) a 3- to 14-membered non-aromatic heterocyclic group,-   (23) a formyl group,-   (24) a carboxy group,-   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,-   (26) a C₆₋₁₄ aryl-carbonyl group,-   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,-   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,-   (29) a C₁₋₆ alkoxy-carbonyl group,-   (30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,    1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),-   (31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,    phenethyloxycarbonyl),-   (32) a carbamoyl group,-   (33) a thiocarbamoyl group,-   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,-   (35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),-   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,    pyridylcarbamoyl, thienylcarbamoyl),-   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group    (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),-   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,-   (39) a C₆₋₁₄ arylsulfonyl group,-   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,    pyridylsulfonyl, thienylsulfonyl),-   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,-   (42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,    1-naphthylsulfinyl, 2-naphthylsulfinyl),-   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,    pyridylsulfinyl, thienylsulfinyl),-   (44) an amino group,-   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,    ethylamino, propylamino, isopropylamino, butylamino, dimethylamino,    diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),-   (46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),-   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,    pyridylamino),-   (48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),-   (49) a formylamino group,-   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,    propanoylamino, butanoylamino),-   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino group (e.g.,    N-acetyl-N-methylamino),-   (52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,    naphthylcarbonylamino),-   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,    ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,    tert-butoxycarbonylamino),-   (54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,    benzyloxycarbonylamino),-   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,    ethylsulfonylamino),-   (56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a    C₁₋₆ alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),-   (57) an optionally halogenated C₁₋₆ alkyl group,-   (58) a C₂₋₆ alkenyl group,-   (59) a C₂₋₆ alkynyl group,-   (60) a C₃₋₁₀ cycloalkyl group,-   (61) a C₃₋₁₀ cycloalkenyl group, and-   (62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, 35 tetrazolyl, triazinyl and the like;and 8- to 14-membered fused polycyclic (preferably bi- or tri-cyclic)aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi- ortri-cyclic) non-aromatic heterocyclic groups such asdihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl,dihydrobenzothiazolyl, dihydrobenzisothiazolyl,dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl,4H-quinolizinyl, indolinyl, isoindolinyl,tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include 20 quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the above-mentioned Substituent Group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from SubstituentGroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl) aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C-₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl) amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl) aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl) amino group (e.g., N-acetyl-N-methylamino) and a(C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl) amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- oralkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxy group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from SubstituentGroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₉ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₉aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from Substituent Group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “hydrocarbon ring” includea C₆₋₁₄ aromatic hydrocarbon ring, C₃₋₁₀ cycloalkane and C₃₋₁₃cycloalkene.

In the present specification, examples of the “C₆₋₁₄ aromatichydrocarbon ring” include benzene and naphthalene.

In the present specification, examples of the “C₃₋₁₀ cycloalkane”include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane and cyclooctane.

In the present specification, examples of the “C₃₋₁₀ cycloalkene”include cyclopropene, cyclobutene, cyclopentene, cyclohexene,cycloheptene and cyclooctene.

In the present specification, examples of the “heterocycle” include anaromatic heterocycle and a non-aromatic heterocycle, each containing, asa ring-constituting atom besides carbon atom, 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, examples of the “aromatic heterocycle”include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “aromatic heterocycle” include5- or 6-membered monocyclic aromatic heterocycles such as thiophene,furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole,tetrazole, triazine and the like; and 8- to 14-membered fused polycyclic(preferably bi- or tri-cyclic) aromatic heterocycles such asbenzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole,benzothiazole, benzisothiazole, benzotriazole, imidazopyridine,thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine,oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine,thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine,oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine,pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole,isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, phenothiazine,phenoxazine and the like.

In the present specification, examples of the “non-aromatic heterocycle”include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms 20 selected from a nitrogen atom, a sulfur atom andan oxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3- to 8-membered monocyclic non-aromatic heterocycles such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepane, diazepane, azepine, azocane, diazocane, oxepane and the like;and 9- to 14-membered fused polycyclic (preferably bi- or tri-cyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-β-carbolise, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the “nitrogen-containingheterocycle” include a heterocycle containing at least one nitrogen atomas a ring-constituting atom, from among the “heterocycle”.

In the present specification, examples of the “5- or 6-memberednitrogen-containing non-aromatic heterocycle” include 5- to 6-memberedgroups containing at least nitrogen atom as ring constituting atom, fromamong the “3- to 8-membered monocyclic non-aromatic heterocycle”.

In the present specification, examples of the “4- to 7-membered ring”include a C₄₋₇ cycloalkane, benzene, a 5- or 6-membered monocyclicaromatic heterocycle and a 4- to 7-membered monocyclic non-aromaticheterocycle.

In the present specification, examples of the “C₄₋₇ cycloalkane” include4- to 7-membered groups from among the “C₃₋₁₀ cycloalkane”.

In the present specification, examples of the “4- to 7-memberedmonocyclic non-aromatic heterocycle” include 4- to 7-membered groupsfrom among the “3- to 8-membered monocyclic non-aromatic heterocycle”.

In the present specification, examples of the “3- to 6-membered cyclicgroup” include a C₃₋₆ cycloalkyl group, phenyl, a 5- or 6-memberedmonocyclic aromatic heterocyclic group and a 3- to 6-membered monocyclicnon-aromatic heterocyclic group.

In the present specification, examples of the “C₃₋₆ cycloalkyl group”include 3- to 6-membered groups from among the “C₃₋₁₀ cycloalkyl group”.

In the present specification, examples of the “3- to 6-memberedmonocyclic non-aromatic heterocyclic group” include 3- to 6-memberedgroups from among the “3- to 8-membered monocyclic non-aromaticheterocyclic group”.

In the present specification, the “mono- or di-C₁₋₆ alkylaminosulfonylgroup” means a sulfonyl group to which the “mono- or di-C₁₋₆ alkylaminogroup” is bonded.

In the present specification, the “3- to 6-membered cyclylsulfonylgroup” means a sulfonyl group to which the “3- to 6-membered cyclicgroup” is bonded.

In the present specification, the “C₁₋₆ alkyl-carbonyl-carbonyl group”means a carbonyl group to which the alkyl-carbonyl “C₁₋₆ group” isbonded.

In the present specification, the “C₁₋₆ alkoxy-carbonyl-carbonyl group”means a carbonyl group to which the “C₁₋₆ alkoxy-carbonyl group” isbonded.

In the present specification, the “mono- or di-C₁₋₆alkyl-carbamoyl-carbonyl group” means a carbonyl group to which the“mono- or di-C₁₋₆ alkyl-carbonyl group” is bonded.

In the present specification, the “3- to 6-membered cyclylcarbonylgroup” means a carbonyl group to which the “3- to 6-membered cyclicgroup” is bonded.

The definition of each symbol used in the formula (I) is explained indetail.

R¹ is an optionally substituted C₁₋₆ alkylsulfonyl group, an optionallysubstituted mono- or di-C₁₋₆ alkylaminosulfonyl group, an optionallysubstituted 3- to 6-membered cyclylsulfonyl group, a formylcarbonylgroup, a carboxycarbonyl group, a carbamoylcarbonyl group, an optionallysubstituted C₁₋₆ alkyl-carbonyl group, an optionally substituted C₁₋₆alkoxy-carbonyl group, an optionally substituted mono- or di-C₁₋₆alkyl-carbamoyl group, an optionally substituted C₁₋₆alkyl-carbonyl-carbonyl group, an optionally substituted C₁₋₆alkoxy-carbonyl-carbonyl group, an optionally substituted mono- ordi-C₁₋₆ alkyl-carbamoyl-carbonyl group or an optionally substituted 3-to 6-membered cyclylcarbonyl group.

Examples of the substituent of the above-mentioned “optionallysubstituted C₁₋₆ alkylsulfonyl group”, “optionally substituted mono- ordi-C₁₋₆ alkylaminosulfonyl group”, “optionally substituted 3- to6-membered cyclylsulfonyl group”, “optionally substituted C₁₋₆alkyl-carbonyl group”, “optionally substituted C₁₋₆ alkoxy-carbonylgroup”, “optionally substituted mono- or di-C₁₋₆ alkyl-carbamoyl group”,“optionally substituted C₁₋₆ alkyl-carbonyl-carbonyl group”, “optionallysubstituted C₁₋₆ alkoxy-carbonyl-carbonyl group”, “optionallysubstituted mono- or di-C₁₋₆ alkyl-carbamoyl-carbonyl group” and“optionally substituted 3- to 6-membered cyclylcarbonyl group” includesubstituents selected from Substituent Group A. The number of thesubstituents is preferably 1 to 3. When the number of the substituentsis 2 or more, the respective substituents may be the same or different.

R¹ is preferably

-   (1) an optionally substituted C₁₋₆ alkylsulfonyl group,-   (2) an optionally substituted 3- to 6-membered cyclylsulfonyl group    (preferably a C₃₋₆ cycloalkylsulfonyl group),-   (3) an optionally substituted mono- or di-C₁₋₆    alkyl-carbamoyl-carbonyl group, or-   (4) an optionally substituted 3- to 6-membered cyclylcarbonyl group    (preferably a C₃₋₆ cycloalkyl-carbonyl group or a 3- to 6-membered    non-aromatic heterocyclylcarbonyl group).

R¹ is more preferably

-   (1) an optionally halogenated C₁₋₆ alkylsulfonyl group (e.g.,    methylsulfonyl, ethylsulfonyl, fluoromethylsulfonyl,    difluoromethylsulfonyl),-   (2) a C₃₋₆ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom),-   (3) a mono- or di-C₁₋₆ alkyl-carbamoyl-carbonyl group (e.g.,    dimethylcarbamoylcarbonyl),-   (4) a C₃₋₆ cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl)    optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    or-   (5) a 3- to 6-membered non-aromatic heterocyclylcarbonyl group    (e.g., tetrahydrofurylcarbonyl).

R¹ is further more preferably

-   (1) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), or-   (2) a C₃₋₆ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom).

R¹ is still more preferably

-   (1) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), or-   (2) a C₃₋₆ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl)    optionally substituted by one halogen atom (e.g., a fluorine atom).

R¹ is particularly preferably a C₃₋₆ cycloalkylsulfonyl group (e.g.,cyclopropylsulfonyl) optionally substituted by one halogen atom (e.g., afluorine atom).

R² and R³ are each independently a hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group or a halogen atom.

Examples of the substituent of the “optionally substituted C₁₋₆ alkylgroup” for R² or R³ include substituents selected from Substituent GroupA. The number of the substituents is preferably 1 to 3. When the numberof the substituents is 2 or more, the respective substituents may be thesame or different.

R² is preferably a hydrogen atom or a halogen atom (e.g., a fluorineatom).

R² is more preferably a hydrogen atom.

R³ is preferably a hydrogen atom or a halogen atom (e.g., a fluorineatom).

R³ is more preferably a hydrogen atom.

X is an optionally substituted methylene group, NR^(a) or an oxygenatom. R^(a) is a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup.

Examples of the substituent of the “optionally substituted methylenegroup” for X and the “optionally substituted C₁₋₆ alkyl group” for R^(a)include substituents selected from Substituent Group A. The number ofthe substituents is preferably 1 to 3. When the number of thesubstituents is 2 or more, the respective substituents may be the sameor different.

X is preferably an optionally substituted methylene group.

X is more preferably

-   (1) a methylene group optionally substituted by 1 or 2 substituents    selected from a C₁₋₆ alkoxy group (e.g., methoxy) and a halogen atom    (e.g., a fluorine atom), or-   (2) a carbonyl group.

X is particularly preferably a methylene group.

Y and Z are each independently a carbon atom, CH or a nitrogen atom.

-   is Z—Y or Z═Y.-   When

is Z═Y, then Y and Z are both carbon atoms, and when

-   is Z—Y, then Y is a carbon atom, CH or a nitrogen atom, and Z is CH    or a nitrogen atom. That is, the partial structure represented by

-   is a partial structure represented by

Preferably, Y is a carbon atom, CH or a nitrogen atom, and Z is a carbonatom or a nitrogen atom. That is, the partial structure represented by

is preferably a partial structure represented by

More preferably, Y is a carbon atom or CH, and Z is a carbon atom or anitrogen atom. That is, the partial structure represented by

is more preferably a partial structure represented by

Further more preferably, Y is a carbon atom, and Z is a carbon atom or anitrogen atom. That is, the partial structure represented by

is further more preferably a partial structure represented by

Particularly preferably, Y is a carbon atom, and Z is a carbon atom.That is, the partial structure represented by

is particularly preferably a partial structure represented by

Ring A is an optionally further substituted 5- or 6-memberednitrogen-containing non-aromatic heterocycle.

The “optionally further substituted 5- or 6-membered nitrogen-containingnon-aromatic heterocycle” for Ring A optionally has additionalsubstituent(s) in addition to the one oxo group on the carbon atomadjacent to Z in the formula (I). Examples of the substituent includethe above-mentioned “substituent”. The number of the substituents ispreferably 1 to 3. When the number of the substituents is 2 or more, therespective substituents may be the same or different.

Ring A is preferably a 5- or 6-membered nitrogen-containing non-aromaticheterocycle (e.g., dihydropyridine, tetrahydropyridine, piperidine,imidazolidine, dihydroimidazole, dihydropyrazole, dihydropyrazine,dihydropyrimidine, tetrahydropyrimidine, hexahydropyrimidine,dihydropyridazine, morpholine) optionally further substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, a        bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the        C₁₋₆ alkyl group is optionally deuterated (e.g., ethyl-d₅,        isopropyl-d₇)) optionally substituted by 1 to 3 substituents        selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a hydroxy group, and        -   (iii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (e) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (f) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (g) a mono- or di-C₁₋₆ alkylamino group (e.g., dimethylamino),        and having one oxo group on the carbon atom adjacent to Z.

Ring A is more preferably

-   (1) a dihydropyridine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, a        bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the        C₁₋₆ alkyl group is optionally deuterated (e.g., ethyl-d₅))        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (e) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (f) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (g) a mono- or di-C₁₋₆ alkylamino group (e.g., dimethylamino),        and having one oxo group on the carbon atom adjacent to Z,-   (2) a tetrahydropyridine ring having one oxo group on the carbon    atom adjacent to Z,-   (3) a piperidine ring optionally further substituted by 1 to 3 C₁₋₆    alkyl groups (e.g., methyl), and having one oxo group on the carbon    atom adjacent to Z,-   (4) an imidazolidine ring optionally further substituted by 1 to 3    C₁₋₆ alkyl groups (e.g., methyl), and having one oxo group on the    carbon atom adjacent to Z,-   (5) a dihydroimidazole ring optionally further substituted by 1 to 3    C₁₋₆ alkyl groups (e.g., methyl, ethyl, isopropyl), and having one    oxo group on the carbon atom adjacent to Z,-   (6) a dihydropyrazole ring optionally further substituted by 1 to 3    C₁₋₆ alkyl groups (e.g., methyl, isopropyl), and having one oxo    group on the carbon atom adjacent to Z,-   (7) a dihydropyrazine ring optionally further substituted by 1 to 3    halogen atoms (e.g., a chlorine atom), and having one oxo group on    the carbon atom adjacent to Z,-   (8) a dihydropyrimidine ring optionally further substituted by 1 to    3 substituents selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the        C₁₋₆ alkyl group is optionally deuterated (e.g., isopropyl-d₇))        optionally substituted by 1 to 3 C₃₋₁₀ cycloalkyl groups (e.g.,        cyclopropyl), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and having one        oxo group on the carbon atom adjacent to Z,-   (9) a tetrahydropyrimidine ring optionally further substituted by 1    to 3 C₁₋₅ alkyl groups (e.g., isopropyl), and having one oxo group    on the carbon atom adjacent to Z,-   (10) a hexahydropyrimidine ring optionally further substituted by 1    to 3 C₁₋₆ alkyl groups (e.g., methyl), and having one oxo group on    the carbon atom adjacent to Z,-   (11) a dihydropyridazine ring optionally further substituted by 1 to    3 C₁₋₅ alkyl groups (e.g., methyl, isopropyl), and having one oxo    group on the carbon atom adjacent to Z, or-   (12) a morpholine ring optionally further substituted by 1 to 3 C₁₋₆    alkyl groups (e.g., methyl), and having one oxo group on the carbon    atom adjacent to Z.

Ring A is further more preferably

-   (1) a dihydropyridine ring optionally substituted by 1 to 3 C₁₋₆    alkyl groups (e.g., methyl, isopropyl), and having one oxo group on    the carbon atom adjacent to Z, or-   (2) a dihydropyrimidine ring optionally substituted by 1 to 3 C₁₋₆    alkyl groups (e.g., isopropyl), and having one oxo group on the    carbon atom adjacent to Z.

Ring A is still more preferably

-   (1) a dihydropyridine ring substituted by one C₁₋₆ alkyl group    (e.g., methyl, isopropyl), and having one oxo group on the carbon    atom adjacent to Z, or-   (2) a dihydropyrimidine ring substituted by one C₁₋₆ alkyl group    (e.g., isopropyl), and having one oxo group on the carbon atom    adjacent to Z.

Ring A is particularly preferably a dihydropyrimidine ring substitutedby one C₁₋₆ alkyl group (e.g., isopropyl), and having one oxo group onthe carbon atom adjacent to Z.

When the partial structure represented by

is a partial structure represented by

then the ring structure for Ring A

is preferably the following ring structures (a1) to (a7):

wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i),R^(j), R^(k), R^(n), R^(o), R^(p) and R^(q) are each independently ahydrogen atom or a substituent.

Examples of the “substituent” for R^(a), R^(b), R^(c), R^(d), R^(e),R^(f), R^(g), R^(h), R^(i), R^(j), R^(k), R^(l), R^(m), R^(n), R^(o),R^(p) or R^(q) include the above-mentioned “substituent”.

In (a1),

-   R^(a) is preferably-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the C₁₋₆    alkyl group is optionally deuterated (e.g., ethyl-d₅)).-   R^(b) is preferably a hydrogen atom.-   R^(c) is preferably-   (1) a hydrogen atom, or-   (2) a halogen atom (e.g., a fluorine atom).

In (a2),

-   R^(d) is preferably-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the C₁₋₆    alkyl group is optionally deuterated (e.g., isopropyl-d₇))    optionally substituted by 1 to 3 C₃₋₁₀ cycloalkyl groups (e.g.,    cyclopropyl), or-   (2) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl).-   R^(e) is preferably-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl).

In (a3),

-   R^(f) is preferably-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl).-   R^(g) is preferably a C₁₋₆ alkyl group (e.g., methyl).

In (a4),

-   R^(h) is preferably a C₁₋₆ alkyl group (e.g., isopropyl).-   R^(i) is preferably a C₁₋₆ alkyl group (e.g., methyl).

In (a5),

-   R^(j) is preferably a C₁₋₆ alkyl group (e.g., isopropyl).-   R^(k) is preferably a hydrogen atom.-   R^(l) is preferably a hydrogen atom.

In (a6),

-   R^(m) is preferably a C₁₋₆ alkyl group (e.g., ethyl).-   R^(n) is preferably a C₁₋₆ alkyl group (e.g., methyl).-   R^(o) is preferably a C₁₋₆ alkyl group (e.g., methyl).

In (a7),

-   R^(p) is preferably a C₁₋₆ alkyl group (e.g., isopropyl).-   R^(q) is preferably a C₁₋₆ alkyl group (e.g., methyl).

When the partial structure represented by

is a partial structure represented by

then the ring structure for Ring A

is preferably the following ring structure (b1):

wherein R^(r) and R^(s) are each independently a hydrogen atom or asubstituent.

Examples of the “substituent” for R^(r) or R^(s) include theabove-mentioned “substituent”.

In (b1),

-   R^(r) is preferably a C₁₋₆ alkyl group (e.g., methyl).-   R^(s) is preferably a hydrogen atom.

When the partial structure represented by

is a partial structure represented by

then the ring structure for Ring A

is preferably the following ring structures (c1) to (c4):

wherein R^(t), R^(u), R^(u), R^(w), R^(x), R^(y), R^(z), R^(aa), R^(bb)and R^(cc) are each independently a hydrogen atom or a substituent.

Examples of the “substituent” for R^(t), R^(u), R^(v), R^(w), R^(x),R^(y), R^(z), R^(aa), R^(bb) or R^(cc) include the above-mentioned“substituent”.

In (c1),

-   R^(t) is preferably-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl).-   R^(u) is preferably a hydrogen atom.-   R^(v) is preferably a hydrogen atom.

In (c2),

-   R^(w) is preferably a C₁₋₆ alkyl group (e.g., methyl).-   R^(x) is preferably a hydrogen atom.

In (c3),

-   R^(y) is preferably a C₁₋₆ alkyl group (e.g., methyl).-   R^(z) is preferably a hydrogen atom.-   R^(aa) is preferably a hydrogen atom.

In (c4),

R^(bb) is preferably a C₁₋₆ alkyl group (e.g., methyl).

-   R^(cc) is preferably a hydrogen atom.

When the partial structure represented by

is a partial structure represented by

then the ring structure for Ring A

is preferably the following ring structures (d1) to (d5):

wherein R^(dd), R^(ee), R^(ff), R^(gg), R^(hh), R^(ii), R^(jj), R^(kk),R^(ll), R^(mm), R^(nn) and R^(oo) are each independently a hydrogen atomor a substituent.

Examples of the “substituent” for R^(dd), R^(ee), R^(ff), R^(gg),R^(hh), R^(ii), R^(jj), R^(kk), R^(ll), R^(mm), R^(nn) or R^(oo) includethe above-mentioned “substituent”.

In (d1),

-   R^(dd) is preferably-   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a fluorine atom, a chlorine atom, a    bromine atom),-   (3) a cyano group,-   (4) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) optionally    substituted by 1 to 3 substituents selected from    -   (i) a halogen atom (e.g., a fluorine atom), and    -   (ii) a hydroxy group,-   (5) a C₁₋₆ alkoxy group (e.g., methoxy),-   (6) a C₁₋₁₀ cycloalkyl group (e.g., cyclopropyl),-   (7) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), or-   (8) a mono- or di-C₁₋₆ alkylamino group (e.g., dimethylamino).-   R^(ee) is preferably-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl).-   R^(ff) is preferably-   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a fluorine atom, a chlorine atom, a    bromine atom), or-   (3) a C₁₋₆ alkyl group (e.g., methyl).

In (d2),

-   R^(gg) is preferably a hydrogen atom.-   R^(hh) is preferably a hydrogen atom.-   R^(ii) is preferably a hydrogen atom.

In (d3),

-   R^(jj) is preferably a halogen atom (e.g., a chlorine atom).-   R^(kk) is preferably a halogen atom (e.g., a chlorine atom).

In (d4),

-   R^(ll) is preferably a C₁₋₆ alkyl group (e.g., methyl).-   R^(mm) is preferably a hydrogen atom.

In (d5),

-   R^(nn) is preferably a C₁₋₆ alkyl group (e.g., methyl, ethyl,    isopropyl).-   R^(oo) is preferably a hydrogen atom.

The above-mentioned ring structure for Ring A is more preferably thefollowing ring structures (a1), (a2) or (d1):

In (a1),

-   R^(a) is more preferably a C₁₋₆ alkyl group (e.g., isopropyl).-   R^(b) is more preferably a hydrogen atom.-   R^(c) is more preferably a hydrogen atom.

In (a2),

-   R^(d) is more preferably a C₁₋₆ alkyl group (e.g., isopropyl).-   R^(e) is more preferably a hydrogen atom.

In (d1),

-   R^(dd) is more preferably a C₁₋₆ alkyl group (e.g., methyl).-   R^(ee) is more preferably a hydrogen atom.-   R^(ff) is more preferably a hydrogen atom.

The above-mentioned ring structure for Ring A is particularly preferablythe following ring structure (a2):

In (a2),

-   R^(d) is particularly preferably a C₁₋₆ alkyl group (e.g.,    isopropyl).-   R^(e) is particularly preferably a hydrogen atom.

L is an optionally substituted methylene group, an oxygen atom, —O-L¹-,-L¹-O— or -L¹-L²-. L¹ and L² are each independently an optionallysubstituted methylene group.

Examples of the substituent of the “optionally substituted methylenegroup” for L, L¹ or L² include substituents selected from SubstituentGroup A. The number of the substituents is preferably 1 to 3. When thenumber of the substituents is 2 or more, the respective substituents maybe the same or different.

L is preferably an optionally substituted methylene group or an oxygenatom.

L is more preferably an optionally substituted methylene group.

L is further more preferably a methylene group.

Ring B is an optionally further substituted 4- to 7-membered ring.

The “optionally further substituted 4- to 7-membered ring” for Ring Boptionally has additional substituent(s) in addition to-L-6-memberedring (containing X, Y and Z) in the formula (I). Examples of thesubstituent include the above-mentioned “substituent”. The number of thesubstituents is preferably 1 to 3. When the number of the substituentsis 2 or more, the respective substituents may be the same or different.

Ring B is preferably a 4- to 7-membered ring (preferably a 5- or6-membered aromatic heterocycle (e.g., benzene, pyridine, thiazole))further substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkyl group (e.g., ethyl),    -   (c) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a C₆₋₁₄ aryl group (e.g., phenyl) (the C₆₋₁₄ aryl group is        optionally fused with a 3- to 8-membered monocyclic non-aromatic        heterocycle (e.g., tetrahydrofuran) (e.g., dihydrobenzofuran))        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom, a chlorine atom),        -   (ii) an optionally halogenated C₁₋₆ alkyl group (e.g.,            methyl, difluoromethyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (e) a 5- to 14-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,        pyridyl, pyrazolyl)) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),    -   (f) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., dihydropyridyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (g) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (h) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy), and        -   (i) a C₂₋₆ alkenyl group (e.g., 2-methyl-1-propenyl).

Ring B is more preferably

-   (1) a benzene ring further substituted by 1 to 3 substituents    selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkyl group (e.g., ethyl),    -   (c) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a C₆₋₁₄ aryl group (e.g., phenyl) (the C₆₋₁₄ aryl group is        optionally fused with a 3- to 8-membered monocyclic non-aromatic        heterocycle (e.g., tetrahydrofuran) (e.g., dihydrobenzofuran))        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom, a chlorine atom),        -   (ii) an optionally halogenated C₁₋₆ alkyl group (e.g.,            methyl, difluoromethyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (e) a 5- to 14-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,        pyridyl, pyrazolyl)) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),    -   (f) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., dihydropyridyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (g) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (h) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy), and    -   (i) a C₂₋₆ alkenyl group (e.g., 2-methyl-1-propenyl),-   (2) a pyridine ring further substituted by 1 to 3 C₆₋₁₄ aryl groups    (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g.,    a fluorine atom), or-   (3) a thiazole ring further substituted by C₆₋₁₄ aryl group(s)    (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g.,    a fluorine atom).

Ring B is further more preferably

-   (1) a benzene ring further substituted by 1 or 2 substituents    selected from    -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or-   (2) a thiazole ring further substituted by C₆₋₁₄ aryl group(s)    (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g.,    a fluorine atom).

Ring B is particularly preferably a benzene ring further substituted by

-   -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a phenyl group optionally substituted by 1 to 3 halogen        atoms (e.g., a fluorine atom).

In compound (I), the configuration based on the carbon atom that —NHR¹is bonded to and the carbon atom that -L-Ring B 30 is bonded to ispreferably cis-form. That is, compound (I) is preferably represented bythe formula (IA) or (IB):

wherein each symbol is as defined above, more preferably represented bythe formula (IA):

wherein each symbol is as defined above.

Preferable embodiments of compound (I) include the following compounds.These compounds are preferably represented by the above formula (IA) or(TB), more preferably represented by the formula (IA).

[Compound A]

Compound (I) wherein

-   R¹ is-   (1) an optionally substituted C₁₋₆ alkylsulfonyl group,-   (2) an optionally substituted 3- to 6-membered cyclylsulfonyl group    (preferably a C₃₋₆ cycloalkylsulfonyl group),-   (3) an optionally substituted mono- or di-C₁₋₆    alkyl-carbamoyl-carbonyl group, or-   (4) an optionally substituted 3- to 6-membered cyclylcarbonyl group    (preferably a C₃₋₆ cycloalkyl-carbonyl group or a 3- to 6-membered    non-aromatic heterocyclylcarbonyl group);-   R² and R³ are both hydrogen atoms;-   X is an optionally substituted methylene group;-   the partial structure represented by

is a partial structure represented by

-   Ring A is an optionally further substituted 5- or 6-membered    nitrogen-containing non-aromatic heterocycle;-   L is an optionally substituted methylene group; and-   Ring B is an optionally further substituted 4- to 7-membered ring.

[Compound B]

Compound (I) wherein

-   R¹ is-   (1) an optionally halogenated C₁₋₆ alkylsulfonyl group (e.g.,    methylsulfonyl, ethylsulfonyl, fluoromethylsulfonyl,    difluoromethylsulfonyl),-   (2) a C₃₋₆ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom),-   (3) a mono- or di-C₁₋₆ alkyl-carbamoyl-carbonyl group (e.g.,    dimethylcarbamoylcarbonyl),-   (4) a C₃₋₆ cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl)    optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    or-   (5) a 3- to 6-membered non-aromatic heterocyclylcarbonyl group    (e.g., tetrahydrofurylcarbonyl);-   R² is a hydrogen atom or a halogen atom (e.g., a fluorine atom);-   R³ is a hydrogen atom or a halogen atom (e.g., a fluorine atom);-   X is-   (1) a methylene group optionally substituted by 1 or 2 substituents    selected from a C₁₋₆ alkoxy group (e.g., methoxy) and a halogen atom    (e.g., a fluorine atom), or-   (2) a carbonyl group;-   the partial structure represented by

20

is a partial structure represented by

-   Ring A is a 5- or 6-membered nitrogen-containing non-aromatic    heterocycle (e.g., dihydropyridine, tetrahydropyridine, piperidine,    imidazolidine, dihydroimidazole, dihydropyrazole, dihydropyrazine,    dihydropyrimidine, tetrahydropyrimidine, hexahydropyrimidine,    dihydropyridazine, morpholine) optionally further substituted by 1    to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, a        bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the        C₁₋₆ alkyl group is optionally deuterated (e.g., ethyl-d₅,        isopropyl-d₇)) optionally substituted by 1 to 3 substituents        selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a hydroxy group, and        -   (iii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (e) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (f) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (g) a mono- or di-C₁₋₆ alkylamino group (e.g., dimethylamino),-   and having one oxo group on the carbon atom adjacent to Z;-   L is a methylene group; and-   Ring B is a 4- to 7-membered ring (preferably a 5- or 6-membered    aromatic heterocycle (e.g., benzene, pyridine, thiazole)) further    substituted by 1 to 3 substituents selected 5 from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkyl group (e.g., ethyl),    -   (c) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a C₆₋₁₄ aryl group (e.g., phenyl) (the C₆₋₁₄ aryl group is        optionally fused with a 3- to 8-membered monocyclic non-aromatic        heterocycle (e.g., tetrahydrofuran) (e.g., dihydrobenzofuran))        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom, a chlorine atom),        -   (ii) an optionally halogenated C₁₋₆ alkyl group (e.g.,            methyl, difluoromethyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (e) a 5- to 14-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,        pyridyl, pyrazolyl)) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),    -   (f) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., dihydropyridyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (g) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (h) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy), and    -   (i) a C₂₋₆ alkenyl group (e.g., 2-methyl-1-propenyl).

[Compound C]

Compound (I) wherein

-   -   R¹ is

-   (1) an optionally halogenated C₁₋₆ alkylsulfonyl group (e.g.,    methylsulfonyl, ethylsulfonyl, fluoromethylsulfonyl,    difluoromethylsulfonyl),

-   (2) a C₃₋₆ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom),

-   (3) a mono- or di-C₁₋₆ alkyl-carbamoyl-carbonyl group (e.g.,    dimethylcarbamoylcarbonyl),

-   (4) a C₃₋₆ cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl)    optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    or

-   (5) a 3- to 6-membered non-aromatic heterocyclylcarbonyl group    (e.g., tetrahydrofurylcarbonyl);

-   R² is a hydrogen atom or a halogen atom (e.g., a fluorine atom);

-   R³ is a hydrogen atom or a halogen atom (e.g., a fluorine atom);

-   X is

-   (1) a methylene group optionally substituted by 1 or 2 substituents    selected from a C₁₋₆ alkoxy group (e.g., methoxy) and a halogen atom    (e.g., a fluorine atom), or

-   (2) a carbonyl group;

-   the partial structure represented by

is a partial structure represented by

-   Ring A is-   (1) a dihydropyridine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, a        bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the        C₁₋₅ alkyl group is optionally deuterated (e.g., ethyl-d₅))        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (e) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (f) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (g) a mono- or di-C₁₋₆ alkylamino group (e.g., dimethylamino),-   and having one oxo group on the carbon atom adjacent to Z,-   (2) a tetrahydropyridine ring having one oxo group on the carbon    atom adjacent to Z,-   (3) a piperidine ring optionally further substituted by 1 to 3 C₁₋₆    alkyl groups (e.g., methyl), and having one oxo group on the carbon    atom adjacent to Z,-   (4) an imidazolidine ring optionally further substituted by 1 to 3    C₁₋₆ alkyl groups (e.g., methyl), and having one oxo group on the    carbon atom adjacent to Z,-   (5) a dihydroimidazole ring optionally further substituted by 1 to 3    C₁₋₆ alkyl groups (e.g., methyl, ethyl, isopropyl), and having one    oxo group on the carbon atom adjacent to Z,-   (6) a dihydropyrazole ring optionally further substituted by 1 to 3    C₁₋₆ alkyl groups (e.g., methyl, isopropyl), and having one oxo    group on the carbon atom adjacent to Z,-   (7) a dihydropyrazine ring optionally further substituted by 1 to 3    halogen atoms (e.g., a chlorine atom), and having one oxo group on    the carbon atom adjacent to Z,-   (8) a dihydropyrimidine ring optionally further substituted by 1 to    3 substituents selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the        C₁₋₆ alkyl group is optionally deuterated (e.g., isopropyl-d₇))        optionally substituted by 1 to 3 C₃₋₁₀ cycloalkyl groups (e.g.,        cyclopropyl), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),-   and having one oxo group on the carbon atom adjacent to Z,-   (9) a tetrahydropyrimidine ring optionally further substituted by 1    to 3 C₁₋₆ alkyl groups (e.g., isopropyl), and having one oxo group    on the carbon atom adjacent to Z,-   (10) a hexahydropyrimidine ring optionally further substituted by 1    to 3 C₁₋₆ alkyl groups (e.g., methyl), and having one oxo group on    the carbon atom adjacent to Z,-   (11) a dihydropyridazine ring optionally further substituted by 1 to    3 C₁₋₆ alkyl groups (e.g., methyl, isopropyl), and having one oxo    group on the carbon atom adjacent to Z, or-   (12) a morpholine ring optionally further substituted by 1 to 3 C₁₋₆    alkyl groups (e.g., methyl), and having one oxo group on the carbon    atom adjacent to Z;-   L is a methylene group; and-   Ring B is-   (1) a benzene ring further substituted by 1 to 3 substituents    selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkyl group (e.g., ethyl),    -   (c) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a C₆₋₁₄ aryl group (e.g., phenyl) (the C₆₋₁₄ aryl group is        optionally fused with a 3- to 8-membered monocyclic non-aromatic        heterocycle (e.g., tetrahydrofuran) (e.g., dihydrobenzofuran))        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom, a chlorine atom),        -   (ii) an optionally halogenated C₁₋₆ alkyl group (e.g.,            methyl, difluoromethyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (e) a 5- to 14-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,        pyridyl, pyrazolyl)) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),    -   (f) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., dihydropyridyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (g) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (h) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy), and    -   (i) a C₂₋₆ alkenyl group (e.g., 2-methyl-1-propenyl),-   (2) a pyridine ring further substituted by 1 to 3 C₆₋₁₄ aryl groups    (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g.,    a fluorine atom), or-   (3) a thiazole ring further substituted by C₆₋₁₄ aryl group(s)    (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g.,    a fluorine atom).

[Compound Ca]

[Compound B] or [Compound C] wherein the ring structure represented by

for Ring A is the following ring structures (a1) to (a7), (b1), (c1) to(c4) or (d1) to (d5)

in (a1),

-   R^(a) is-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the C₁₋₆    alkyl group is optionally deuterated (e.g., ethyl-d₅));-   R^(b) is a hydrogen atom; and-   R^(c) is-   (1) a hydrogen atom, or-   (2) a halogen atom (e.g., a fluorine atom);

in (a2),

-   R^(d) is-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) (the C₁₋₆    alkyl group is optionally deuterated (e.g., isopropyl-d₇))    optionally substituted by 1 to 3 C₃₋₁₀ cycloalkyl groups (e.g.,    cyclopropyl), or-   (2) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl); and-   R^(e) is-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl);

in (a3),

-   R^(f) is-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl); and-   R^(g) is a C₁₋₆ alkyl group (e.g., methyl);

in (a4),

-   R^(h) is a C₁₋₆ alkyl group (e.g., isopropyl); and-   R^(i) is a C₁₋₆ alkyl group (e.g., methyl);

in (a5),

-   R^(j) is a C₁₋₆ alkyl group (e.g., isopropyl);-   R^(k) is a hydrogen atom; and-   R^(l) is a hydrogen atom;

in (a6),

-   R^(m) is a C₁₋₆ alkyl group (e.g., ethyl);-   R^(n) is a C₁₋₆ alkyl group (e.g., methyl); and-   R^(o) is a C₁₋₆ alkyl group (e.g., methyl);

in (a7),

-   R^(p) is a C₁₋₆ alkyl group (e.g., isopropyl); and-   R^(q) is a C₁₋₆ alkyl group (e.g., methyl);

in (b1),

-   R^(r) is a C₁₋₆ alkyl group (e.g., methyl); and-   R^(s) is a hydrogen atom;

in (c1),

-   R^(t) is-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl);-   R^(u) is a hydrogen atom; and-   R^(v) is a hydrogen atom;

in (c2),

-   R^(w) is a C₁₋₆ alkyl group (e.g., methyl); and-   R^(x) is a hydrogen atom;

in (c3),

-   R^(y) is a C₁₋₆ alkyl group (e.g., methyl);-   R^(z) is a hydrogen atom; and-   R^(aa) is a hydrogen atom;

in (c4),

-   R^(bb) is a C₁₋₆ alkyl group (e.g., methyl); and-   R^(cc) is a hydrogen atom;

in (d1),

-   R^(dd) is-   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a fluorine atom, a chlorine atom, bromine    atom),-   (3) a cyano group,-   (4) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl) optionally    substituted by 1 to 3 substituents selected from    -   (i) a halogen atom (e.g., a fluorine atom), and    -   (ii) a hydroxy group,-   (5) a C₁₋₆ alkoxy group (e.g., methoxy),-   (6) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),-   (7) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), or-   (8) a mono- or di-C₁₋₆ alkylamino group (e.g., dimethylamino);-   R^(ee) is-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl); and-   R^(ff) is-   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a fluorine atom, a chlorine atom, a    bromine atom), or-   (3) a C₁₋₆ alkyl group (e.g., methyl);

in (d2),

-   R^(gg) is a hydrogen atom;-   R^(hh) is a hydrogen atom; and-   R^(ii) is a hydrogen atom;

in (d3),

-   R^(j) is a halogen atom (e.g., a chlorine atom); and-   R^(kk) is a halogen atom (e.g., a chlorine atom);

in (d4),

-   R^(ll) is a C₁₋₆ alkyl group (e.g., methyl); and-   R^(mm) is a hydrogen atom;

in (d5),

-   R^(nn) is a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl); and-   R^(oo) is a hydrogen atom.

[Compound D]

Compound (I) wherein

-   R¹ is-   (1) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), or-   (2) a C₃₋₆ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom);-   R² is a hydrogen atom;-   R³ is a hydrogen atom;-   X is a methylene group;-   the partial structure represented by

is a partial structure represented by

-   Ring A is-   (1) a dihydropyridine ring optionally substituted by 1 to 3 C₁₋₆    alkyl groups (e.g., methyl, isopropyl), and having one oxo group on    the carbon atom adjacent to Z, or-   (2) a dihydropyrimidine ring optionally substituted by 1 to 3 C₁₋₆    alkyl groups (e.g., isopropyl), and having one oxo group on the    carbon atom adjacent to Z;-   L is a methylene group; and-   Ring B is-   (1) a benzene ring further substituted by 1 or 2 substituents    selected from    -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or-   (2) a thiazole ring further substituted by C₆₋₁₄ aryl group(s)    (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g.,    a fluorine atom).

[Compound Da]

[Compound D] wherein the ring structure represented by

for Ring A is the following ring structures (a1), (a2) or (d1)

in (a1),

-   R^(a) is a C₁₋₆ alkyl group (e.g., isopropyl);-   R^(b) is a hydrogen atom; and-   R^(c) is a hydrogen atom;

in (a2),

-   R^(d) is a C₁₋₆ alkyl group (e.g., isopropyl); and-   R^(e) is a hydrogen atom;

in (d1),

-   R^(dd) is a C₁₋₆ alkyl group (e.g., methyl);-   R^(ee) is a hydrogen atom; and-   R^(ff) is a hydrogen atom.

[Compound E]

Compound (I) wherein

R¹ is a C₃₋₆ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl)optionally substituted by one halogen atom (e.g., a fluorine atom);

-   R² is a hydrogen atom;-   R³ is a hydrogen atom;-   X is a methylene group;-   the partial structure represented by

-   is a partial structure represented by

-   Ring A is a dihydropyrimidine ring substituted by one C₁₋₆ alkyl    group (e.g., isopropyl), and having one oxo group on the carbon atom    adjacent to Z;-   L is a methylene group; and-   Ring B is a benzene ring further substituted by    -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a phenyl group optionally substituted by 1 to 3 halogen        atoms (e.g., a fluorine atom).

[Compound Ea]

[Compound E] wherein the ring structure represented by

for Ring A is the following ring structure (a2)

in (a2),

-   R^(d)is a C₁₋₆ alkyl group (e.g., isopropyl); and-   R^(e) is a hydrogen atom.

Specific examples of compound (I) include the compounds of thebelow-mentioned Examples 1 to 23 and 25 to 216.

Specifically, compound (I) is preferablyN-[(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropanesulfonamideor a salt thereof (Example 176),1-fluoro-N-[(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamideor a salt thereof (Example 180), orN-{(5R,6S)-4-oxo-3-(propan-2-yl)-5-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin-6-yl}cyclopropanesulfonamideor a salt thereof (Example 195).

As a salt of a compound represented by the formula (I), apharmacologically acceptable salt is preferable, and examples 5 of suchsalt include a salt with inorganic base, a salt with organic base, asalt with inorganic acid, a salt with organic acid, a salt with basic oracidic amino acid and the like.

Preferable examples of the salt with inorganic base include alkali metalsalts such as sodium salt, potassium salt and the like, alkaline earthmetal salts such as calcium salt, magnesium salt and the like, aluminumsalt, ammonium salt and the like.

Preferable examples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine,tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine,cyclohexylamine, benzylamine, dicyclohexylamine,N,N-dibenzylethylenediamine and the like.

Preferable examples of the salt with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferable examples of the salt with organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like.

Preferable examples of the salt with basic amino acid include salts witharginine, lysine, ornithine and the like. Preferable examples of thesalt with acidic amino acid include salts with aspartic acid, glutamicacid and the like.

The production method of the compound of the present invention isexplained below.

The raw material compound and reagent used and the compound obtained ineach step in the following production method may be each in a form of asalt, and examples of such salt include those similar to the salts ofthe compound represented by the formula (I), and the like.

When the compound obtained in each step is a free form, it can beconverted to the objective salt according to a method known per se. Whenthe compound obtained in each step is a salt, it can be converted to theobjective free form or the other salt according to a method known perse.

The compound obtained in each step can be used directly as the reactionmixture or as a crude product for the next reaction. Alternatively, thecompound obtained in each step can be isolated and purified from areaction mixture according to a method known per se, for example, aseparation means such as concentration, crystallization,recrystallization, distillation, solvent extraction, fractionaldistillation, column chromatography and the like.

When the raw material compound and reagent used in each step arecommercially available, the commercially available product can also beused directly.

In the reaction in each step, while the reaction time varies dependingon the kind of the reagent and solvent to be used, it is generally 1min-48 hr, preferably 10 min-8 hr, unless otherwise specified.

In the reaction in each step, while the reaction temperature variesdepending on the kind of the reagent and solvent to be used, it isgenerally −78° C.-300° C., preferably −78° C.-150° C., unless otherwisespecified.

In the reaction in each step, while the pressure varies depending on thekind of the reagent and solvent to be used, it is generally 1 atm-20atm, preferably 1 atm-3 atm, unless otherwise specified.

Microwave synthesizer such as Initiator manufactured by Biotage and thelike may be used for the reaction in each step. While the reactiontemperature varies depending on the kind of the reagent and solvent tobe used, it is generally room temperature −300° C., preferably 50°C.-250° C., unless otherwise specified. While the reaction time variesdepending on the kind of the reagent and solvent to be used, it isgenerally 1 min-48 hr, preferably 1 min-8 hr, unless otherwisespecified.

In the reaction in each step, the reagent is used in an amount of 0.5equivalents-20 equivalents, preferably 0.8 equivalents-5 equivalents,relative to the substrate, unless otherwise specified. When the reagentis used as a catalyst, the reagent is used in an amount of 0.001equivalent-1 equivalent, preferably 0.01 equivalent-0.2 equivalent,relative to the substrate. When the reagent is used as a reactionsolvent, the reagent is used in a solvent amount.

Unless otherwise specified, the reaction in each step is carried outwithout solvent, or by dissolving or suspending the raw materialcompound in a suitable solvent. Examples of the solvent include thosedescribed in Examples and the following solvents.

-   alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol    and the like;-   ethers: diethyl ether, diphenyl ether, tetrahydrofuran,    1,2-dimethoxyethane and the like;-   aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;-   saturated hydrocarbons: cyclohexane, hexane and the like; amides:    N,N-dimethylformamide, N-methylpyrrolidone and the like;-   halogenated hydrocarbons: dichloromethane, carbon tetrachloride and    the like;-   nitriles: acetonitrile and the like;-   sulfoxides: dimethyl sulfoxide and the like;-   aromatic organic bases: pyridine and the like;-   anhydrides: acetic anhydride and the like;-   organic acids: formic acid, acetic acid, trifluoroacetic acid and    the like;-   inorganic acids: hydrochloric acid, sulfuric acid and the like;    esters: ethyl acetate and the like;-   ketones: acetone, methyl ethyl ketone and the like;-   water.

The above-mentioned solvent can be used in a mixture of two or morekinds thereof in an appropriate ratio.

When a base is used for the reaction in each step, examples thereofinclude those described in Examples and the following bases.

-   inorganic bases: sodium hydroxide, magnesium hydroxide, sodium    carbonate, calcium carbonate, sodium hydrogen carbonate and the    like;-   organic bases: triethylamine, diethylamine, pyridine,    4-dimethylaminopyridine, N,N-dimethylaniline,    1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,    imidazole, piperidine and the like;-   metal alkoxides: sodium ethoxide, potassium tert-butoxide and the    like;-   alkali metal hydrides: sodium hydride and the like;-   metal amides: sodium amide, lithium diisopropylamide, lithium    hexamethyldisilazide and the like;-   organic lithiums: n-butyllithium and the like.

When an acid or an acid catalyst is used for the reaction in each step,examples thereof include those described in Examples and the followingacids and acid catalysts. inorganic acids: hydrochloric acid, sulfuricacid, nitric acid, hydrobromic acid, phosphoric acid and the like;organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; Lewisacid: boron trifluoride diethyl ether complex, zinc iodide, anhydrousaluminum chloride, anhydrous zinc chloride, anhydrous iron chloride andthe like.

Unless otherwise specified, the reaction in each step is carried outaccording to a method known per se, for example, the method described inJikken Kagaku Kouza, 5th Edition, vol.13-19 (the Chemical Society ofJapan ed.); Shin Jikken Kagaku Kouza, vol.14-15 (the Chemical Society ofJapan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze,Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism andEssence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESESCollective Volume I-VII (John Wiley & Sons Inc.); Modern OrganicSynthesis in the Laboratory A Collection of Standard ExperimentalProcedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive HeterocyclicChemistry III, Vol. 1-Vol.14 (Elsevier Japan); Strategic Applications ofNamed Reactions in Organic Synthesis (translated by Kiyoshi Tomioka,Kagakudojin); Comprehensive Organic Transformations (VCH PublishersInc.), 1989, or the like, or the method described in Examples.

In each step, the protection or deprotection reaction of an functionalgroup is carried out according to a method known per se, for example,the method described in “Protective Groups in Organic Synthesis, 4thEd”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M.Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski), orthe like, or the method described in Examples.

Examples of the protecting group for a hydroxy group of an alcohol andthe like and a phenolic hydroxy group include ether-type protectinggroups such as methoxymethyl ether, benzyl ether,tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like;carboxylate ester-type protecting groups such as acetate ester and thelike; sulfonate ester-type protecting groups such as methanesulfonateester and the like; carbonate ester-type protecting groups such astert-butylcarbonate and the like, and the like.

Examples of the protecting group for a carbonyl group of an aldehydeinclude acetal-type protecting groups such as dimethylacetal and thelike; cyclic acetal-type protecting groups such as 1,3-dioxane and thelike, and the like.

Examples of the protecting group for a carbonyl group of a ketoneinclude ketal-type protecting groups such as dimethylketal and the like;cyclic ketal-type protecting groups such as 1,3-dioxane and the like;oxime-type protecting groups such as O-methyloxime and the like;hydrazone-type protecting groups such as N,N-dimethylhydrazone and thelike, and the like.

Examples of the protecting group for a carboxyl group include ester-typeprotecting groups such as methyl ester and the like; amide-typeprotecting groups such as N,N-dimethylamide and the like, and the like.

Examples of the protecting group for a thiol include ether-typeprotecting groups such as benzyl thioether and the like; ester-typeprotecting groups such as thioacetate ester, thiocarbonate,thiocarbamate and the like, and the like.

Examples of the protecting group for an amino group and an aromaticheterocycle such as imidazole, pyrrole, indole and the like includecarbamate-type protecting groups such as benzyl carbamate and the like;amide-type protecting groups such as acetamide and the like; alkylamine-type protecting groups such as N-triphenylmethylamine and thelike; sulfonamide-type protecting groups such as methanesulfonamide andthe like, and the like.

The protecting groups can be removed according to a method known per se,for example, by employing a method using acid, base, ultraviolet rays,hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide(e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, areduction method, and the like.

When reduction reaction is carried out in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt;hydrogen; formic acid; triethylsilane and the like. When carbon-carbondouble bond or triple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar's catalyst and the like may be employed.

When oxidation reaction is carried out in each step, examples of theoxidizing agent to be used include peroxides such as m-chloroperbenzoicacid (mCPBA), hydrogen peroxide, tert-butylhydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodates such as sodium periodate and the like;hypervalent iodine reagents such as iodosylbenzene and the like;reagents containing manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents containing chromium such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When radical cyclization reaction is carried out in each step, examplesof the radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4-4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. Examples of the radical reagent to be used includetributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane,diphenylsilane, samarium iodide and the like.

When Wittig reaction is carried out in each step, examples of the Wittigreagent to be used include alkylidene phosphoranes and the like. Thealkylidene phosphoranes can be prepared according to a method known perse, for example, by reacting a phosphonium salt with a strong base.

When Horner-Emmons reaction is carried out in each step, examples of thereagent to be used include phosphonoacetates such as methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like;and bases such as alkali metal hydrides, organic lithiums and the like.

When Friedel-Crafts reaction is carried out in each step, a combinationof a Lewis acid and an acid chloride or a combination of a Lewis acidand an alkylating agent (e.g., an alkyl halide, an alcohol, an olefinetc.) is used as a reagent. Alternatively, an organic acid or aninorganic acid can also be used instead of a Lewis acid, and ananhydride such as acetic anhydride and the like can also be used insteadof an acid chloride.

When aromatic nucleophilic substitution reaction is carried out in eachstep, a nucleophile (e.g., an amine, imidazole etc.) and a base (e.g.,an organic base etc.) are used as a reagent.

When nucleophilic addition reaction by a carbo anion, nucleophilic1,4-addition reaction (Michael addition reaction) by a carbo anion ornucleophilic substitution reaction by a carbo anion is carried out ineach step, and examples of the base to be used for generation of thecarbo anion include organic lithiums, metal alkoxides, inorganic bases,organic bases and the like.

When Grignard reaction is carried out in each step, examples of theGrignard reagent to be used include arylmagnesium halides such asphenylmagnesium bromide and the like; and alkylmagnesium halides such asmethylmagnesium bromide and the like. The Grignard reagent can beprepared according to a method known per se, for example, by reacting analkyl halide or an aryl halide with a metal magnesium in an ether ortetrahydrofuran as a solvent.

When Knoevenagel condensation reaction is carried out in each step, acompound having an activated methylene group with two electronwithdrawing groups (e.g., malonic acid, diethyl malonate, malononitrileetc.) and a base (e.g., an organic base, a metal alkoxide, an inorganicbase) are used as a reagent.

When Vilsmeier-Haack reaction is carried out in each step, phosphorylchloride and an amide derivative (e.g., N,N-dimethylformamide etc.) areused as a reagent.

When azidation reaction of an alcohol, an alkyl halide or a sulfonate iscarried out in each step, examples of the azidating agent to be usedinclude diphenylphosphorylazide (DPPA), trimethylsilylazide, sodiumazide and the like. For example, for the azidation reaction of analcohol, a method using diphenylphosphorylazide and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method usingtrimethylsilylazide and a Lewis acid, and the like are employed.

When reductive amination reaction is carried out in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, examples of the carbonyl compound to beused include paraformaldehyde, aldehydes such as acetaldehyde and thelike, and ketones such as cyclohexanone and the like. When the substrateis a carbonyl compound, examples of the amine to be used includeammonia, primary amines such as methylamine and the like; secondaryamines such as dimethylamine and the like, and the like.

When Mitsunobu reaction is carried out in each step, an azodicarboxylate(e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate(DIAD) etc.) and triphenylphosphine are used as a reagent.

When esterification reaction, amidation reaction or urea formationreaction is carried out in each step, examples of the reagent to be usedinclude acyl halides such as acid chlorides, acid bromides and the like;activated carboxylic acids such as acid anhydrides, activated esters,sulfates and the like. Examples of the activating agent of thecarboxylic acid include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloriden-hydrate (DMT-MM) and the like; carbonate condensing agents such as1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide(DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOPreagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent);thionyl chloride; lower alkyl haloformates such as ethyl chloroformateand the like; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphorate (HATU); sulfuric acid; combinations thereof andthe like. When carbodiimide condensing agent is used, an additive suchas 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like may be added to the reactionsystem.

When coupling reaction is carried out in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and the like;nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and thelike; rhodium compounds such as tris(triphenylphosphine)rhodium(III)chloride and the like; cobalt compounds; copper compounds such as copperoxide, copper(I) iodide and the like; platinum compounds and the like.In addition, a base can be added to the reaction system, and examplesthereof include inorganic bases and the like.

When thiocarbonylation reaction is carried out in each step, phosphoruspentasulfide is typically used as the thiocarbonylating agent.Alternatively, a reagent having a1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g.,2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) etc.) can also be used instead of phosphoruspentasulfide.

When Wohl-Ziegler reaction is carried out in each step, examples of thehalogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NES), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. In addition, the reaction can be accelerated bysubjecting a radical initiator such as heat, light, benzoyl peroxide,azobisisobutyronitrile and the like to the reaction system reaction.

When halogenation reaction of a hydroxy group is carried out in eachstep, examples of the halogenating agent to be used include hydrohalicacids and acid halides of inorganic acids, specifically, hydrochloricacid, thionyl chloride, phosphorus oxychloride and the like forchlorination, 48% hydrobromic acid and the like for bromination. Inaddition, a method for producing an alkyl halide by reacting an alcoholwith triphenylphosphine and carbon tetrachloride or carbon tetrabromideor the like can be employed. Alternatively, a method for producing analkyl halide via two steps comprising converting an alcohol to thecorresponding sulfonate, and then reacting the sulfonate with lithiumbromide, lithium chloride or sodium iodide can also be employed.

When Arbuzov reaction is carried out in each step, examples of thereagent to be used include alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite, tri(isopropyl)phosphite and the like.

When sulfonate esterification reaction is carried out in each step,examples of the sulfonating agent to be used include methanesulfonylchloride, p-toluenesulfonyl chloride, methanesulfonic anhydride,p-toluenesulfonic anhydride and the like.

When hydrolysis reaction is carried out in each step, an acid or a baseis used as a reagent. For acid hydrolysis reaction of tert-butyl ester,formic acid, triethylsilane and the like may be added toreductively-trap tert-butyl cation which is by-produced.

When dehydration reaction is carried out in each step, examples of thedehydrating agent to be used include sulfuric acid, diphosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

Among compound (6) used in the below-mentioned Scheme 2, compound (6)-1can be produced from compound (1) according to the method shown in thefollowing Scheme 1. In the scheme, LG¹ and LG² are each independently aleaving group, R⁴ and R⁵ are each independently an optionallysubstituted C₁₋₆ alkyl group, and the other each symbol is as definedabove.

Examples of the “leaving group ” for LG¹ or LG² include halogen atoms,optionally halogenated C₁₋₆ alkylsulfonyloxy groups (e.g.,methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy),C₆₋₁₄ arylsulfonyloxy groups optionally substituted by C₁₋₆ alkylgroup(s) (e.g., benzenesulfonyloxy, toluenesulfonyloxy) and the like.

Examples of the substituent of the “optionally substituted C₁₋₆ alkylgroup” for R⁴ or R⁵ include substituents selected from Substituent GroupA. The number of the substituents is preferably 1 to 3. When the numberof the substituents is 2 or more, the respective substituents may be thesame or different.

Compound (1) may be a commercially available product, or can be producedaccording to a method known per se or a method analogous thereto.

Compound (3) can be produced by subjecting compound (1) to anucleophilic substitution reaction with compound (2) in the presence ofa base. Compound (2) may be a commercially available product, or can beproduced according to a method known per se or a method analogousthereto. Examples of the base to be used include alkali metal hydrides,organic lithiums and the like.

Compound (5) can be produced by subjecting compound (3) to a couplingreaction with compound (4). Compound (4) may be a commercially availableproduct, or can be produced according to a method known per se or amethod analogous thereto.

Compound (8) used in the below-mentioned Scheme 3 can be produced fromcompound (6) according to the method shown in the following Scheme 2. Inthe scheme, each symbol is as defined above.

Compound (7) can be produced by subjecting compound (6) to acondensation reaction in the presence of a base. Examples of the base tobe used include inorganic bases, organic bases, alkali metal hydridesand the like.

Compound (8) can be produced by subjecting compound (7) to adecarboxylation reaction in the presence of an acid. Examples of theacid to be used include inorganic acids, organic acids and the like.

Compound (I) can be produced from compound (8) according to the methodshown in the following Scheme 3. In the scheme, LG³ and LG⁴ are eachindependently a leaving group, and the other each symbol is as definedabove.

Examples of the “leaving group” for LG³ or LG⁴ include those exemplifiedas the “leaving group” represented by LG¹ or LG².

Compound (10) can be produced by subjecting compound (8) to anucleophilic substitution reaction with compound (9) in the presence ofa base. Examples of the base to be used include alkali metal hydrides,organic lithiums and the like. Alternatively, compound (10) can also beproduced by two step reaction, i.e., by converting compound (8) into thecorresponding enamine, and then reacting the enamine with compound (9).Compound (9) may be a commercially available product, or can be producedaccording to a method known per se or a method analogous thereto.

Examples of the amine to be used for the enamine formation includepyrrolidine, morpholine, N,N-dimethylhydrazine and the like. A base maybe added to the reaction system of the enamine and compound (9).Examples of the base include alkali metal hydrides, organic lithiums andthe like. In addition, a catalyst may be added to the reaction system inorder to promote the reaction. Examples of the catalyst to be usedinclude tetrabutylammonium iodide and the like.

Compound (11) can be produced by subjecting compound (10) to a reductiveamination reaction. Examples of the reducing agent to be used includesodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formicacid and the like. Examples of the amine to be used include ammonia andthe like. In addition, a metal catalyst may be added to the reactionsystem. Examples of the catalyst to be used include iridium catalystsand the like. Alternatively, Compound (11) can also be produced by twostep reaction, i.e., by converting compound (10) into the correspondingoxime, and then subjecting the oxime to a reduction reaction. Examplesof the amine to be used for the oxime formation include hydroxylamine,O-methylhydroxylamine and the like. Examples of the reducing agent to beused include boranes such as borane tetrahydrofuran complex and thelike, sodium borohydride and the like. In addition, a metal catalyst maybe added to the reaction system. Examples of the catalyst to be usedinclude molybdenum trioxide and the like.

Compound (I) can be produced by subjecting compound (11) to acondensation reaction with compound (12) or compound (13). Thecondensation reaction includes amidation reaction, urea formationreaction, carbamation reaction, sulfonamidation reaction, sulfamidationreaction, sulfamatation reaction and the like. Examples of compound (13)to be used include acyl halides such as acid chlorides, acid bromides,alkyl chloroformates, carbamoyl chlorides and the like, sulfonylchlorides, sulfamoyl chlorides, alkyl chlorosulfates and the like.Compound (12) and compound (13) may be a commercially available product,or can be produced according to a method known per se or a methodanalogous thereto.

In the thus-obtained compound (I), an intramolecular functional groupcan also be converted to an object functional group by a combination ofchemical reactions known per se. Examples of the chemical reactioninclude oxidation reaction, reduction reaction, alkylation reaction,acylation reaction, ureation reaction, hydrolysis reaction, aminationreaction, esterification reaction, aryl coupling reaction, deprotectionreaction and the like.

In the above-mentioned production method, when a starting compound hasan amino group, a carboxyl group, a hydroxy group, a carbonyl group or amercapto group as a substituent, a protecting group generally used inthe peptide chemistry may be introduced into these groups, and theobject compound can be obtained by removing the protecting group asnecessary after the reaction.

Compound (I) obtained by the above-mentioned production method can beisolated and purified by a known means, such as solvent extraction,liquid conversion, phase transfer, crystallization, recrystallization,chromatography and the like.

When compound (I) contains optical isomer, stereoisomer, regio isomerand rotamer, these compounds are also included in compound (I), and eachcan be obtained as a single product by a synthesis method or aseparation method known per se. For example, when an optical isomerexists in compound (I), an optical isomer resolved from the compound isalso encompassed in compound (I).

Here, an optical isomer can be produced by a method known per se.

Compound (I) may be a crystal.

A crystal of compound (I) (hereinafter sometimes to be abbreviated asthe crystal of the present invention) can be produced by crystallizingcompound (I), by applying a crystallization method known per se.

In the present specification, the melting point means a melting pointmeasured, for example, by micro melting point apparatus (Yanako, MP-500Dor Buchi, B-545), DSC (differential scanning calorimetry analysis)apparatus (METTLER TOLEDO, DSC1) and the like.

Generally, the melting point sometimes varies depending on themeasurement device, measurement condition and the like. The crystal inthe present specification may be a crystal showing a melting pointdifferent from the values described in the present specification as longas the difference is within a general error range.

The crystal of the present invention is superior in the physicochemicalproperties (e.g., melting point, solubility, stability) and biologicalproperties (e.g., pharmacokinetics (absorbability, distribution,metabolism, excretion), efficacy expression), and is extremely useful asa medicament.

Compound (I) may be used as a prodrug. A prodrug of the compound (I)means a compound which is converted to the compound (I) of the presentinvention with a reaction due to an enzyme, an gastric acid, etc. underthe physiological condition in the living body, that is, a compoundwhich is converted to the compound (I) of the present invention withoxidation, reduction, hydrolysis, etc. according to an enzyme; acompound which is converted to the compound (I) of the present inventionby hydrolysis etc. due to gastric acid, etc.

A prodrug of compound (I) may be a compound obtained by subjecting anamino group in compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting an hydroxy group incompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group incompound (I) to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification andmethylamidation, etc.) and the like. Any of these compounds can beproduced from compound (I) by a method known per se.

A prodrug for compound (I) may also be one which is converted intocompound (I) under a physiological condition, such as those described inIYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design ofMolecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

In the present specification, a prodrug may form a salt, and as suchsalt, those exemplified as a salt of the compound represented by theabove-mentioned formula (I) can be mentioned.

Compound (I) may be labeled with an isotope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸F,³⁵S, ¹²⁵I) and the like.

Compound (I) labeled with or substituted by an isotope can be used, forexample, as a tracer used for Positron Emission Tomography (PET) (PETtracer), and is useful in the field of medical diagnosis and the like.

Furthermore, compound (I) may be a hydrate or a non-hydrate, or anon-solvate (e.g., anhydride), or a solvate (e.g., hydrate).

Compound (I) also encompasses a deuterium conversion form wherein ¹H isconverted to ²H(D).

Furthermore, compound (I) may be a pharmaceutically acceptable cocrystalor cocrystal salt. The cocrystal or cocrystal salt means a crystallinesubstance constituted with two or more special solids at roomtemperature, each having different physical properties (e.g., structure,melting point, melting heat, hygroscopicity, solubility and stability).The cocrystal or cocrystal salt can be produced by a cocrystallizationmethod known per se.

Compound (I) or a prodrug thereof (hereinafter sometimes to be simplyabbreviated as the compound of the present invention) can be used as itis or in the form of a pharmaceutical composition (also referred to as amedicament) by mixing with a pharmacologically acceptable carrier etc.to mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse,swine, monkey) as an agent for the prophylaxis or treatment of variousdiseases mentioned below.

As pharmacologically acceptable carriers, various organic or inorganiccarrier substances conventionally used as preparation materials can beused. These are incorporated as excipient, lubricant, binder anddisintegrant for solid preparations; or solvent, solubilizing agent,suspending agent, isotonicity agent, buffer and soothing agent forliquid preparations; and the like; and preparation additives such aspreservative, antioxidant, colorant, sweetening agent and the like canbe added as necessary.

Preferable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, starch, gelatinated starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose, sodiumcarboxymethylcellulose, gum arabic, pullulan, light anhydrous silicicacid, synthetic aluminum silicate and magnesium alumino metasilicate.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc and colloidal silica.

Preferable examples of the binder include gelatinated starch, sucrose,gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the disintegrant include lactose, sucrose,starch, carboxymethylcellulose, calcium carboxymethylcellulose,croscarmellose sodium, sodium carboxymethyl starch, light anhydroussilicic acid and low-substituted hydroxypropylcellulose.

Preferable examples of the solvent include water for injection,physiological brine, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferable examples of the solubilizing agent include polyethyleneglycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate,ethanol, trisaminomethane, cholesterol, triethanolamine, sodiumcarbonate, sodium citrate, sodium salicylate and sodium acetate.

Preferable examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate and the like; hydrophilic polymers such as poly(vinylalcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like, polysorbates; and polyoxyethylenehydrogenated castor oil.

Preferable examples of the isotonicity agent include sodium chloride,glycerol, D-mannitol, D-sorbitol and glucose.

Preferable examples of the buffer include buffers of phosphate, acetate,carbonate, citrate etc.

Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include p-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Preferable examples of the antioxidant include sulfite salts andascorbate salts.

Preferable examples of the colorant include aqueous food tar colors(e.g., food colors such as Food Color Red Nos. 2 and 3, Food ColorYellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like foodcolors), water insoluble lake dyes (e.g., aluminum salt of theabove-mentioned aqueous food tar color), natural dyes (e.g., β-carotene,chlorophyll, red iron oxide) and the like.

Preferable examples of the sweetening agent include saccharin sodium,dipotassium glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the above-mentioned pharmaceuticalcomposition include oral preparations such as tablet (includingsugar-coated tablet, film-coated tablet, sublingual tablet, orallydisintegrating tablet, buccal tablet), capsule (including soft capsule,microcapsule), pill, granule, powder, troche, syrup, liquid, emulsion,suspension, aerosol, films (e.g., orally disintegrable films, oralmucosa-adhesive film) and the like; and parenteral agents such asinjection (e.g., subcutaneous injection, intravenous injection,intramuscular injection, intraperitoneal injection, drip infusion),external preparation (e.g., transdermal absorption type preparation,ointment, lotion, adhesive preparation), suppository (e.g., rectalsuppository, vaginal suppository), pellet, nasal preparation, pulmonarypreparation (inhalant), eye drop and the like. The compound andmedicament of the present invention can be respectively safelyadministered orally or parenterally (e.g., intrarectal, intravenous,intraarterial, intramuscular, subcutaneous, intraorgan, intranasal,intradermal, instillation, intracerebral, intravaginal, intraperitoneal,intratumoral, proximal tumor administrations, and administration to thelesion).

These preparations may be a release control preparation (e.g.,sustained-release microcapsule) such as an immediate-releasepreparation, a sustained-release preparation and the like.

The pharmaceutical composition can be produced according to a methodconventionally used in the field of pharmaceutical formulation, forexample, the method described in the Japanese Pharmacopoeia, and thelike.

While the content of the compound of the present invention in thepharmaceutical composition of the present invention varies depending onthe dosage form, dose of the compound of the present invention and thelike, it is, for example, about 0.1 to 100 wt %.

When an oral preparation is produced, coating may be applied wherenecessary for the purpose of taste masking, enteric solubility orsustainability.

Examples of the coating base used for coating include sugar coatingbase, water-soluble film coating base, enteric film coating base, andsustained-release film coating base.

As the sugar coating base, sucrose is used, and one or more kindsselected from talc, and the precipitated calcium carbonate, gelatin, gumarabic, pullulan, carnauba wax and the like may be further used incombination.

Examples of the water-soluble film coating base include cellulosepolymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, methylhydroxyethylcellulose and the like;synthetic polymers such as polyvinyl acetal diethylaminoacetate,aminoalkylmethacrylate copolymer E [Eudragit E (trade name)],polyvinylpyrrolidone and the like; and polysaccharides such as pullulanand the like.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, cellulose acetate phthalate and the like;acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L(trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (tradename)], methacrylic acid copolymer S [Eudragit S (trade name)] and thelike; and naturally-occurring substances such as shellac and the like.

Examples of the sustained-release film coating base include cellulosepolymers such as ethylcellulose and the like; and acrylic acid polymerssuch as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name)],ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE(trade name)] and the like.

Two or more kinds of the above-mentioned coating bases may be used in amixture at an appropriate ratio. In addition, for example, lightshielding agents such as titanium oxide, red ferric oxide and the likemay also be used during coating.

Since the compound of the present invention shows low toxicity (e.g.,acute toxicity, chronic toxicity, genetic toxicity, reproductivetoxicity, cardiotoxicity, carcinogenicity) and less side effects, it canbe used as a prophylactic or therapeutic agent, or diagnostic agent forvarious diseases in mammals (e.g., human, bovine, horse, dog, cat,monkey, mouse, rat).

The compound of the present invention has an excellent an orexin type 2receptor agonist activity, and may treat, prevent or ameliorate the riskof various neurological and psychiatric diseases associated with anorexin type 2 receptor. The compound of the present invention is usefulas an agent for the prophylaxis or treatment of various diseases such asnarcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome,narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomniasyndrome accompanied by daytime hypersomnia (e.g., Kleine Levinsyndrome, major depression with hypersomnia, Lewy body dementia,Parkinson's disease, progressive supranuclear paralysis, Prader-Willisyndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pickdisease type C, brain contusion, cerebral infarction, brain tumor,muscular dystrophy, multiple sclerosis, acute disseminatedencephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis,Wernicke's encephalitis, limbic encephalitis, Hashimoto'sencephalopathy), coma, loss of consciousness, obesity (e.g., malignantmastocytosis, exogenous obesity, hyperinsulinar obesity, hyperplasmicobesity, hypop hyseal adiposity, hypoplasmic obesity, hypothyroidobesity, hypothalamic obesity, symptomatic obesity, infantile obesity,upper body obesity, alimentary obesity, hypogonadal obesity, systemicmastocytosis, simple obesity, central obesity), insulin resistancesyndrome, Alzheimer's disease, disturbance of consciousness such as comaand the like, side effects and complications due to anesthesia, sleepdisturbance, sleep problem, insomnia, Intermittent sleep, nocturnalmyoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleepdisorder of alternating worker, sleep disorder, night terror,depression, major depression, sleepwalking disease, enuresis, sleepdisorder, Alzheimer's dusk, diseases associated with circadian rhythm,fibromyalgia, condition arising from decline in the quality of sleep,overeating, obsessive compulsive eating disorder, obesity-relateddisease, hypertension, diabetes, elevated plasma insulin concentrationand insulin resistance, hyperlipidemia, hyperlipemia, endometrialcancer, breast cancer, prostate cancer, colorectal cancer, cancer,osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones,cardiac disease, abnormal heartbeat, arrhythmia, myocardial infarction,congestive cardiac failure, cardiac failure, coronary heart disease,cardiovascular disorder, sudden death, polycysticovarian disease,craniopharingioma, Froelich's syndrome, growth hormone deficient, normalmutant short stature, Turner's syndrome, children suffering from acutelymphoblastic leukemia, syndrome X, reproductive hormone abnormality,declining fertility, infertility, male gonadal function decline, sexualand reproductive dysfunction such as female male hirsutism, fetaldefects associated with pregnant women obesity, gastrointestinalmotility disorders such as obesity-related gastroesophageal reflux,obesity hypoventilation syndrome (Pickwick syndrome), respiratorydiseases such as dyspnea, inflammation such as systemic inflammation ofthe vascular system, arteriosclerosis, hypercholesterolemia,hyperuricemia, lower back pain, gall bladder disease, gout, kidneycancer, risk of secondary outcomes of obesity such as lowering the riskof left ventricular hypertrophy, migraine pain, headache, neuropathicpain, Parkinson's disease, psychosis, schizophrenia, facial flushing,night sweats, diseases of the genital/urinary system, diseases relatedto sexual function or fertility, dysthymic disorder, bipolar disorder,bipolar I disorder, bipolar II disorder, cyclothymic disorder, acutestress disorder, agoraphobia, generalized anxiety disorder, obsessivedisorder, panic attack, panic disorder, posttraumatic stress disorder,separation anxiety disorder, social phobia, anxiety disorder, acuteneurological and psychiatric disorders such as cardiac bypass surgeryand post-transplant cerebral deficit, stroke, ischemic stroke, cerebralischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiacarrest, hypoglycemic nerve injury, Huntington's disease, amyotrophiclateral sclerosis, multiple sclerosis, eye damage, retinopathy,cognitive impairment, muscle spasm, tremor, epilepsy, disordersassociated with muscle spasticity, delirium, amnestic disorder,age-related cognitive decline, schizoaffective disorder, delusionaldisorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue,medication-induced Parkinsonism syndrome, Jill-do La Tourette'ssyndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia,dyskinesia, attention deficit hyperactivity disorder (ADHD), behaviordisorder, urinary incontinence, withdrawal symptoms, trigeminalneuralgia, hearing loss, tinnitus, nerve damage, retinopathy, maculardegeneration, vomiting, cerebral edema, pain, bone pain, arthralgia,toothache, cataplexy, and traumatic brain injury.

Particularly, the compound of the present invention is useful as anagent for the prophylaxis or treatment of narcolepsy, idiopathichypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndromeaccompanied by narcolepsy-like symptoms, hypersomnia syndromeaccompanied by daytime hypersomnia (e.g., Parkinson's disease,Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer's disease,obesity, insulin resistance syndrome, cardiac failure, diseases relatedto bone loss, sepsis, disturbance of consciousness such as coma and thelike, side effects and complications due to anesthesia, and the like, oranesthetic antagonist.

While the dose of the compound of the present invention varies dependingon the subject of administration, administration route, target disease,symptom and the like, for example, when the compound of the presentinvention is administered orally or parenterally to an adult patient,its dose is for example, about 0.01 to 100 mg/kg body weight per dose,preferably 0.1 to 50 mg/kg body weight per dose and more preferably 0.5to 20 mg/kg body weight per dose. This amount is desirably administeredin one to 3 portions daily.

The compound of the present invention can be used in combination withother drugs (hereinafter to be abbreviated as concomitant drug).

By combining the compound of the present invention and a concomitantdrug, a superior effect, for example,

-   (1) the dose can be reduced as compared to single administration of    the compound of the present invention or a concomitant drug,-   (2) the drug to be combined with the compound of the present    invention can be selected according to the condition of patients    (mild case, severe case and the like),-   (3) the period of treatment can be set longer by selecting a    concomitant drug having different action and mechanism from the    compound of the present invention,-   (4) a sustained treatment effect can be designed by selecting a    concomitant drug having different action and mechanism from the    compound of the present invention,-   (5) a synergistic effect can be afforded by a combined use of the    compound of the present invention and a concomitant drug, and the    like, can be achieved.

In the present specification, the compound of the present invention anda concomitant drug used in combination are referred to as the“combination agent of the present invention”.

When using the combination agent of the present invention, theadministration time of the compound of the present invention and theconcomitant drug is not restricted, and the compound of the presentinvention or a pharmaceutical composition thereof, or the concomitantdrug or a pharmaceutical composition thereof can be administered to anadministration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the dose clinically used, and can be appropriately selecteddepending on an administration subject, administration route, disease,combination and the like.

The administration mode of the combination agent of the presentinvention and the concomitant drug is not particularly limited, and thecompound of the present invention and the concomitant drug only need tobe combined on administration. Examples of such administration modeinclude the following: (1) administration of a single preparationobtained by simultaneously processing the compound of the presentinvention and the concomitant drug, (2) simultaneous administration oftwo kinds of preparations of the compound of the present invention andthe concomitant drug, which have been separately produced, by the sameadministration route, (3) administration of two kinds of preparations ofthe compound of the present invention and the concomitant drug, whichhave been separately produced, by the same administration route in astaggered manner, (4) simultaneous administration of two kinds ofpreparations of the compound of the present invention and theconcomitant drug, which have been separately produced, by 5 differentadministration routes, (5) administration of two kinds of preparationsof the compound of the present invention and the concomitant drug, whichhave been separately produced, by different administration routes in astaggered manner (e.g., administration in the order of the compound ofthe present invention and the concomitant drug, or in the reverse order)and the like.

The dose of the concomitant drug can be appropriately determined basedon the dose employed in clinical situations. The mixing ratio of thecompound of the present invention and a concomitant drug can beappropriately determined depending on the administration subject,administration route, target disease, symptom, combination and the like.

For example, the content of the compound of the present invention in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 0.01 to about 100 wt %,preferably from about 0.1 to about 50 wt %, further preferably fromabout 0.5 to about 20 wt %, based on the whole preparation.

The content of the concomitant drug in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to about 100 wt %, preferably from about 0.1 toabout 50 wt %, further preferably from about 0.5 to about 20 wt %, basedon the whole preparation.

The content of additives such as a carrier and the like in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 1 to about 99.99 wt %,preferably from about 10 to about 90 wt %, based on the preparation.

Similar contents may be employed even when the compound of the presentinvention and a concomitant drug are separately formulated intopreparations.

Examples of the concomitant drug include the followings. A therapeuticdrug for narcolepsy (e.g., methylphenidate, amphetamine, pemoline,phenelzine, protriptyline, sodium oxybate, modafinil, caffeine),antiobesity drug (amphetamine, benzfetamine, bromocriptine, bupropion,diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide,mazindol, methamphetamine, octreotide, octreotide, orlistat,phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa(registered trade mark), phenylpropanolamine, pramlintide,propylhexedrine, recombinant leptin, sibutramine, topiramate,zimelidine, zonisamide, Lorcaserin, metformin), acetylcholine esteraseinhibitor (e.g., donepezil, rivastigmine, galanthamine, zanapezil,idebenone, tacrine), antidementia agent (e.g., memantine), inhibitor ofβ amyloid protein production, secretion, accumulation, aggregationand/or deposition, β secretase inhibitor (e.g.,6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin,6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin,2-(N,N-dimethylamino)methyl-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methylbiphenyl-4-yl)methoxytetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(2′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(3′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,an optically active form thereof, a salt thereof and a hydrate thereof,OM99-2 (WO01/00663)), 65 secretase inhibitor, β amyloid proteinaggregation inhibitor (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368(National Publication of International Patent Application No.11-514333), PPI-558 (National Publication of International PatentApplication No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1),283-289)), β amyloid vaccine, β amyloid-degrading enzyme and the like,brain function enhancer (e.g., aniracetam, nicergoline), therapeuticdrug for Parkinson's disease [(e.g., dopamine receptor agonist (e.g.,L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline,amantadine), monoamine oxidase enzyme (MAO) inhibitor (e.g., deprenyl,selegiline, remacemide, riluzole), anticholinergic agent (e.g.,trihexyphenidyl, biperiden), COMT inhibitor (e.g., entacapone)],therapeutic drug for amyotrophic lateral sclerosis (e.g., riluzole etc.,neurotrophic factor), therapeutic drug for abnormal behavioraccompanying progress of dementia, wandering and the like (e.g.,sedative, anti-anxiety drug), apoptosis inhibitor (e.g., CPI-1189,IDN-6556, CEP-1347), neuronal differentiation-regenerate promoter (e.g.,leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853,prosaptide,5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline,6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindoleand an optically active form, salt or hydrate thereof), non-steroidalantiinflammatory agents (meloxicam, tenoxicam, indomethacin, ibuprofen,celecoxib, rofecoxib, aspirin, indomethacin etc.), steroid drug(dexamethasone, hexestrol, cortisone acetate etc.), disease-modifyinganti-rheumatic drug (DMARDs), anti-cytokine drug (e.g., TNF inhibitor,MAP kinase inhibitor), therapeutic agent for incontinence, frequenturination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride,propiverine hydrochloride), phosphodiesterase inhibitor (e.g.,sildenafil(citrate)), dopamine agonist (e.g., apomorphine),antiarrhythmic drugs (e.g., mexiletine), sex hormone or a derivativethereof (e.g., progesterone, estradiol, estradiol benzoate), therapeuticagent for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin,calcitonin salmon, estriol, ipriflavone, pamidronate disodium,alendronate sodium hydrate, incadronate disodium), parathyroid hormone(PTH), calcium receptor antagonists, therapeutic drug for insomnia(e.g., benzodiazepines medicament, non-benzodiazepines medicament,melatonin agonist, orexin receptor antagonists), therapeutic drug forschizophrenia (e.g., typical antipsychotic agents such as haloperidoland the like; atypical antipsychotic agents such as clozapine,olanzapine, risperidone, aripiprazole and the like; medicament acting onmetabotropic glutamate receptor or ion channel conjugated-type glutamatereceptor; phosphodiesterase inhibitor), benzodiazepines medicament(chlordiazepoxide, diazepam, potassium clorazepate, lorazepam,clonazepam, alprazolam etc.), L-type calcium channel inhibitor(pregabalin etc.), tricyclic or tetracyclic antidepressant (imipraminehydrochloride, amitriptyline hydrochloride, desipramine hydrochloride,clomipramine hydrochloride etc.), selective serotonin reuptake inhibitor(fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide,sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalateetc.), serotonin-noradrenaline reuptake inhibitor (venlafaxinehydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochlorideetc.), noradrenaline reuptake inhibitor (reboxetine mesylate etc.),mirtazapine, trazodone hydrochloride, nefazodone hydrochloride,bupropion hydrochloride, setiptiline maleate, 5-HT_(1A) agonist,(buspirone hydrochloride, tandospirone citrate, osemozotan hydrochlorideetc.), 5-HT_(2A) antagonist, 5-HT_(2A) inverse agonist, 5-HT₃ antagonist(cyamemazine etc.), heart non-selective β inhibitor (propranololhydrochloride, oxprenolol hydrochloride etc.), histamine H₁ antagonist(hydroxyzine hydrochloride etc.), CRF antagonist, other antianxiety drug(meprobamate etc.), tachykinin antagonist (MK-869, saredutant etc.),medicament that acts on metabotropic glutamate receptor, CCK antagonist,β3 adrenaline antagonist (amibegron hydrochloride etc.), GAT-1 inhibitor(tiagabine hydrochloride etc.), N-type calcium channel inhibitor,carbonic anhydrase II inhibitor, NMDA glycine moiety agonist, NMDAantagonist (memantine etc.), peripheral benzodiazepine receptor agonist,vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1aantagonist, phosphodiesterase inhibitor, opioid antagonist, opioidagonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3,T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcyprominesulfate, moclobemide etc.), therapeutic drug for bipolar disorder(lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamateetc.), cannabinoid CB1 antagonist (rimonabant etc.), FAAH inhibitor,sodium channel inhibitor, anti-ADHD drug (methylphenidate hydrochloride,methamphetamine hydrochloride etc.), therapeutic drug for alcoholism,therapeutic drug for autism, therapeutic drug for chronic fatiguesyndrome, therapeutic drug for spasm, therapeutic drug for fibromyalgiasyndrome, therapeutic drug for headache, therapeutic drug for quittingsmoking, therapeutic drug for myasthenia gravis, therapeutic drug forcerebral infarction, therapeutic drug for mania, therapeutic drug forhypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia,therapeutic drug for autonomic ataxia, therapeutic drug for male andfemale sexual dysfunction, therapeutic drug for migraine, therapeuticdrug for pathological gambler, therapeutic drug for restless legssyndrome, therapeutic drug for substance addiction, therapeutic drug foralcohol-related syndrome, therapeutic drug for irritable bowel syndrome,therapeutic drug for lipid abnormality such as cholesterol-lowering drug(statin series (pravastatin sodium, atorvastatin, simvastatin,rosuvastatin etc.), fibrate (clofibrate etc.), squalene synthetaseinhibitor), therapeutic drug for abnormal behavior or suppressant ofdromomania due to dementia (sedatives, antianxiety drug etc.),therapeutic drug for diabetes, therapeutic agent for diabeticcomplications, therapeutic drug for hypertension, therapeutic drug forhypotension, diuretic, chemotherapeutic agent, immunotherapeutic agent,antithrombotic agent, anti-cancer agent and the like.

Two or more kinds of the above-mentioned concomitant drug may be used ina mixture at an appropriate ratio.

When the compound of the present invention is applied to each of theabove-mentioned diseases, it can also be used in combination withbiologics (e.g., antibody drug, nucleic acid or nucleic acid derivative,aptamer drug, vaccine preparation), or can be used in combination with agene therapy method and the like, or can also be used in combinationwith a treatment in psychiatric field without using drugs.

Examples of the antibody drug and vaccine preparation include vaccinepreparation against angiotensin II, vaccine preparation against CETP,CETP antibody, antibody against TNFα antibody and other cytokines,amyloid β vaccine preparation, vaccine for type 1 diabetes (e.g.,DIAPEP-277 of Peptor), anti-HIV antibody and HIV vaccine preparation, aswell as antibodies or vaccine preparations against cytokines,renin-angiotensin type enzymes and products thereof, antibodies orvaccine preparations against enzymes or proteins involved in blood lipidmetabolism, antibodies or vaccines relating to enzymes and proteinsinvolved in blood coagulation or fibrinolysis system, antibodies orvaccine preparations against proteins involved in sugar metabolism andinsulin resistance, and the like. In addition, it can be used incombination with biologics relating to growth factors such as GH, IGFand the like.

Examples of the gene therapy method include a treatment method usinggene relating to cytokine, renin-angiotensin type enzyme and productthereof, G protein, G protein conjugated receptor and phosphorylatingenzyme thereof, a treatment method using a DNA decoy such as NFκB decoyand the like, a treatment method using antisense, a treatment methodusing a gene relating to an enzyme or protein involved in blood lipidmetabolism (e.g., a gene relating to metabolism, excretion andabsorption of cholesterol or triglyceride or HDL-cholesterol or bloodphospholipid), a treatment method using a gene relating to an enzyme orprotein involved in angiogenesis therapy for peripheral vascularobstruction and the like (e.g., growth factors such as HGF, VEGF etc.),a treatment method using a gene relating to a protein involved inglucose metabolism and insulin resistance, antisense against cytokinessuch as TNF etc., and the like.

Examples of the treatment method in the psychiatric field without usingdrug include modified electroconvulsive therapy, deep brain stimulationtherapy, repetitive transcranial magnetic stimulation therapy,psychotherapy including cognitive behavioral therapy and the like.

The compound of the present invention can also be used in combinationwith various organ regeneration methods such as cardiac regeneration,renal regeneration, pancreatic regeneration, revascularization and thelike, cell transplantation therapy utilizing bone marrow cells (bonemarrow-derived mononuclear cell, myelogenic stem cell), or artificialorgan utilizing tissue engineering (e.g., artificial blood vessel,cardiomyocyte sheet).

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples.However, the examples do not limit the present invention and theexamples can be modified within the scope of the present invention.

The “room temperature” in the following Examples is generally about 10°C. to about 35° C. The ratio for mixed solvent is, unless otherwisespecified, a volume mixing ratio 35 and % means wt % unless otherwisespecified.

The elution by column chromatography in the Examples was performed underthe observation by TLC (Thin Layer Chromatography) unless otherwisespecified. In the observation by TLC, 60 F₂54 manufactured by Merck wasused as a TLC plate, the solvent used as an elution solvent in columnchromatography was used as an eluent, and UV detector was used for thedetection. In silica gel column chromatography, the indication of NHmeans use of aminopropylsilane-bonded silica gel and the indication ofDIOL means use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silicagel. In preparative HPLC (high performance liquid chromatography), theindication of C18 means use of octadecyl-bonded silica gel. The ratiofor elution solvent is, unless otherwise specified, a volume mixingratio.

For the analysis of ¹H NMR, ACD/SpecManager (trade name) software andthe like were used. Peaks of a hydroxyl group, an amino group and thelike, having very mild proton peak, are not sometimes described.

MS was measured by LC/MS. As the ionization method, ESI method, or APCImethod was used. The data indicates actual measured value (found). Whilemolecular ion peak is generally observed, a fragment ion is sometimesobserved. In the case of a salt, a molecular ion peak or fragment ionpeak of free form is generally observed.

In the following Examples, the following abbreviations are used.

-   MS: mass spectrum-   M: mol concentration-   N: normality-   CDCl₃: deuterochloroform-   DMSO-d₆: deuterodimethyl sulfoxide-   ¹H NMR: proton nuclear magnetic resonance-   LC/MS: liquid chromatograph mass spectrometer-   ESI: electronspray ionization-   APCI: atmospheric pressure chemical ionization-   HATU:    (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaneiminium    hexafluorophosphate-   IPE: isopropyl ether-   DIPEA: N,N-diisopropylethylamine-   DMF: N,N-dimethylformamide-   THF: tetrahydrofuran-   DME: 1,2-dimethoxyethane-   MeOH: methanol-   EtOH: ethanol-   t-AmOH: 2-methyl-2-butanol-   CH₃CN: acetonitrile-   TEA: triethylamine-   TMSCl: trimethylsilyl chloride-   LDA: lithium diisopropylamide-   LHMDS: lithium hexamethyldisilazide-   NBS: N-bromosuccinimide-   TBAI: tetrabutylammonium iodide-   XPhos Pd G2:    chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)-   XPhos Pd G3:    (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)    methanesulfonate-   MP-Carbonate: microporous triethylammonium-   methylpolystyrenecarbonate

Example 1rac-N-{(3S,4S)-4-[([1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamideA) 6-bromopyridin-2-ol

To a mixture of 2-bromo-6-methoxypyridine (4.64 g), sodium iodide (18.5g) and CH₃CN (120 ml) was added TMSCl (13.4 g) at 0° C. The mixture wasstirred at 50° C. for 5 hr. The mixture was poured into saturatedaqueous sodium hydrogencarbonate solution at 0° C., and extracted withethyl acetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (3.58 g). MS: [M+H]⁺173.8.

B) methyl (6-bromo-2-oxopyridin-1(2H)-yl)acetate

To a mixture of 6-bromopyridin-2-ol (3.58 g) and THF (40 ml) was addedlithium 2-methylpropan-2-olate (1.73 g) at room temperature. Thereaction mixture was stirred for 15 min, and methyl bromoacetate (15.7g) was added thereto. The mixture was refluxed for 2 hr, and thereaction solution was concentrated. To the obtained residue was addedethyl acetate, and the mixture was washed with water, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (4.57g).

MS: [M+H]⁺245.8. C) ethyl(2E)-3-[1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]propa-2-enoate

A mixture of methyl (6-bromo-2-oxopyridin-1(2H)-yl)acetate (4.57 g),ethyl acrylate (9.30 g), DIPEA (7.20 g), palladium(2+) diacetate (0.334g), tris(2-methylphenyl)phosphine (0.678 g) and CH₃CN (45 ml) wasdivided into 3 batches, and each was irradiated with microwave at 150°C. for 1 hr. The reaction solutions were combined, and concentratedunder reduced pressure. To the residue was added ethyl acetate, and theimpurities were removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (2.76g).

MS: [M+H]⁺266.0. D) ethyl3-[1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]propanoate

A mixture of ethyl(2E)-3-[1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]propa-2-enoate(2.76 g), 10% palladium on carbon (60 mg) and MeOH (50 ml) was stirredunder normal hydrogen atmosphere at room temperature for 5 hr. Thecatalyst was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (2.65g).

MS: [M+H]⁺267.9. E)4-[([1,1′-biphenyl]-3-yl)methyl]-2H-quinolizine-3,6(1H,4H)-dione

To a mixture of ethyl3-[1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]propanoate(500 mg) and THF (10 ml) was added 5 M sodium methanolate MeOH solution(0.412 ml) at room temperature. After stirred for 30 min, the reactionsolution was concentrated. To the obtained residue was added conc.hydrochloric acid (10 ml), and the mixture was refluxed for 2 hr, andthe reaction solution was concentrated under reduced pressure. To amixture of the obtained residue and CH₃CN (10 mL) was added pyrrolidine(266 mg) at room temperature. After stirred for 1 hr, the reactionsolution was concentrated. To the obtained residue was added a solutionof TBAI (69.1 mg), and 3-(bromomethyl)biphenyl (231 mg) in CH₃CN (10mL). The mixture was stirred at room temperature for 15 min, and then at70° C. for 2 hr. To the mixture was added water, and the reactionsolution was concentrated. To the obtained residue was added ethylacetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (75.7mg).

MS: [M+H]⁺330.2.

F)6-[([1,1′-biphenyl]-3-yl)methyl]-7-(hydroxyimino)-6,7,8,9-tetrahydro-4H-quinolizin-4-one

To a mixture of4-[([1,1′-biphenyl]-3-yl)methyl]-2H-quinolizine-3,6(1H,4H)-dione (75.7mg) and EtOH (1 ml) were added hydroxylamine hydrochloride (63.9 mg) andsodium acetate (113 mg) at room temperature. The mixture was refluxedfor 10 min, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (DIOL, ethylacetate/hexane) to give the title compound (72.0 mg).

MS: [M+H]⁺345.2. G)rac-(6S,7S)-7-amino-6-[([1,1′-biphenyl]-3-yl)methyl]-6,7,8,9-tetrahydro-4H-quinolizin-4-one

To a mixture of6-[([1,1′-biphenyl]-3-yl)methyl]-7-(hydroxyimino)-6,7,8,9-tetrahydro-4H-quinolizin-4-one(72.0 mg), molybdenum(6+) trioxide (45.1 mg) and MeOH (1 ml) was addedsodium borohydride (39.5 mg) at room temperature. The reaction mixturewas stirred for 30 min, and molybdenum(6+) trioxide (45.1 mg) and sodiumborohydride (39.5 mg) were added thereto. After stirred for 30 min, thereaction solution was concentrated. To the obtained residue was addedethyl acetate, and the mixture was washed with water. The aqueous layerwas extracted with ethyl acetate, and the organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the title compound.

MS: [M+H]⁺331.2. H)rac-N-{(3S,4S)-4-[([1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

To a mixture ofrac-(6S,7S)-7-amino-6-[([1,1′-biphenyl]-3-yl)methyl]-6,7,8,9-tetrahydro-4H-quinolizin-4-one(69.1 mg), TEA (25.4 mg) and THF (1 ml) was added methanesulfonicanhydride (36.4 mg) at room temperature. After stirred for 15 min, thereaction solution was concentrated. The residue was purified by silicagel column chromatography (DIOL, ethyl acetate/hexane) to give the titlecompound (42.1 mg). ¹H NMR (400 MHz, CDCl₃) δ 2.06-2.17 (1H, m),2.24-2.36 (1H, m), 2.61 (3H, s), 2.94-3.23 (4H, m), 3.77-3.92 (1H, m),4.08 (1H, d, J=9.3 Hz), 5.44-5.58 (1H, m), 6.00-6.08 (1H, m), 6.47 (1H,d, J=8.9 Hz), 7.28-7.70 (10H, m).

Example 5rac-N-{(3S,4S)-4-[([1,1′-biphenyl]-3-yl)methyl]-7-bromo-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamideA) ethyl3-[5-bromo-1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]propanoate

To a mixture of ethyl3-[1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]propanoate(1.28 g) and CH₃CN (10 ml) was added NBS (852 mg) at room temperature.The mixture was stirred for 2 hr, and the obtained solid was collectedby filtration, and washed with cooled CH₃CN to give the title compound(874 mg).

MS: [M+H]⁺345.9. B) 7-bromo-2H-quinolizine-3,6(1H,4H)-dione

To a mixture of ethyl3-[5-bromo-1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]propanoate(2.95 g) and toluene (85 ml) was added potassium tert-butoxide (1.43 g)at 0° C. The mixture was stirred at 0° C. for 1 hr. To the mixture wasadded 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. A mixture of the residue and 6 M hydrochloric acid (30 ml) wasstirred at 100° C. for 3 hr, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (1.78 g).

MS: [M+H]⁺242.0. C)4-[([1,1′-biphenyl]-3-yl)methyl]-7-bromo-2H-quinolizine-3,6(1H,4H)-dione

To a mixture of 7-bromo-2H-quinolizine-3,6(1H,4H)-dione (55 mg) andCH₃CN (1 mL) was added pyrrolidine (32.3 mg) at room temperature. Thereaction mixture was stirred for 1 hr, and concentrated under reducedpressure. To the obtained residue was added a solution of TBAI (16.8 mg)and 3-(bromomethyl)biphenyl (56.1 mg) in CH₃CN (1 mL). The mixture wasstirred at room temperature for 15 min, and then at 70° C. for 1 hr. Tothe reaction solution was added water, and the mixture was stirred for30 min, and concentrated under reduced pressure. To the residue wasadded ethyl acetate, and the mixture was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (28.8mg).

MS: [M+H]⁺408.1. D)6-[([1,1′-biphenyl]-3-yl)methyl]-3-bromo-7-(hydroxyimino)-6,7,8,9-tetrahydro-4H-quinolizin-4-one

To a mixture of4-[([1,1′-biphenyl]-3-yl)methyl]-7-bromo-2H-quinolizine-3,6(1H,4H)-dione(34.8 mg) and EtOH (0.5 ml) were added hydroxylamine hydrochloride (23.7mg) and sodium acetate (42.0 mg) at room temperature. After refluxed for10 min, the reaction solution was concentrated. To the obtained residuewas added ethyl acetate, and the mixture was washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give the title compound (36.1 mg).

MS: [M+H]⁺423.2. E)rac-(6S,7S)-7-amino-6-[([1,1′-biphenyl]-3-yl)methyl]-3-bromo-6,7,8,9-tetrahydro-4H-quinolizin-4-one

To a mixture of6-[([1,1′-biphenyl]-3-yl)methyl]-3-bromo-7-(hydroxyimino)-6,7,8,9-tetrahydro-4H-quinolizin-4-one(36.1 mg), molybdenum(6+) trioxide (18.4 mg) and MeOH (0.5 ml) was addedsodium borohydride (16.1 mg) at room temperature. The mixture wasstirred for 15 min, water was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the title compound.

MS: [M+H]⁺409.2. F)rac-N-{(3S,4S)-4-[([1,1′-biphenyl]-3-yl)methyl]-7-bromo-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

To a mixture ofrac-(6S,7S)-7-amino-6-[([1,1′-biphenyl]-3-yl)methyl]-3-bromo-6,7,8,9-tetrahydro-4H-quinolizin-4-one(34.9 mg), TEA (10.4 mg) and THF (0.5 ml) was added methanesulfonicanhydride (14.9 mg) at room temperature. After stirred for 15 min, thereaction solution was concentrated. The residue was purified by silicagel column chromatography (DIOL, ethyl acetate/hexane), and the obtainedsolid was washed with ethyl acetate/IPE to give the title compound (18.2mg). ¹H NMR (400 MHz, CDCl₃) δ 2.08-2.19 (1H, m), 2.23-2.37 (1H, m),2.56 (3H, s), 2.94-3.18 (3H, m), 3.18-3.27 (1H, m), 3.79-3.90 (1H, m),3.92-4.02 (1H, m), 5.46-5.59 (1H, m), 5.99 (1H, d, J=7.8 Hz), 7.33-7.50(5H, m), 7.51-7.61 (3H, m), 7.63-7.74 (2H, m).

Example 6rac-N-{(3S,4S)-4-[([1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

A mixture ofrac-N-{(3S,4S)-4-[([1,1′-biphenyl]-3-yl)methyl]-7-bromo-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamide(15.5 mg), trimethylboroxin (12.0 mg),[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.33 mg),potassium carbonate (11.0 mg) and DME (0.3 ml) was irradiated withmicrowave at 110° C. for 30 min. The reaction solution was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to give the title compound(12.2 mg). ¹H NMR (400 MHz, CDCl₃) δ 2.06-2.20 (4H, m), 2.21-2.37 (1H,m), 2.58 (3H, s), 2.91-3.26 (4H, m), 3.75-3.87 (1H, m), 4.02 (1H, d,J=9.4 Hz), 5.50-5.61 (1H, m), 5.98 (1H, d, J=7.0 Hz), 7.16 (1H, d, J=7.0Hz), 7.32-7.69 (9H, m).

Example 10rel-N-{(3S,4S)-4-[([1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamidewith shorter retention time

rac-N-{(3S,4S)-4-[([1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamide(57 mg) was resolved by HPLC (column: CHIRALPAK ID, 50 mmID×500 mmL,manufactured by Daicel Chemical Industries, mobile phase:hexane/2-propanol=200/800) to give a compound with shorter retentiontime. The obtained compound was suspended in IPE, and the solid wascollected by filtration to give the title compound (17.5 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.82 (3H, s), 1.88-1.98 (1H, m), 2.01-2.13(1H, m), 2.78-2.88 (2H, m), 2.89 (3H, s), 2.96-3.08 (1H, m), 3.25 (1H,dd, J=14.2, 5.4 Hz), 3.56-3.70 (1H, m), 5.38-5.46 (1H, m), 5.98 (1H, d,J=7.0 Hz), 7.15 (2H, d, J=6.7 Hz), 7.26 (1H, t, J=7.6 Hz), 7.31-7.38(2H, m), 7.39-7.47 (3H, m), 7.53-7.59 (3H, m).

Example 50(2S)-N-{(3SR,4SR)-4-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamideA) (2,3′-difluoro[1,1′-biphenyl]-3-yl)methanol

To a mixture of (3-bromo-2-fluorophenyl)methanol (5.0 g), DME (50 ml)and water (10 ml) were added (3-fluorophenyl)boronic acid (4.09 g),potassium carbonate (6.74 g) and XPhos Pd G2 (0.096 g) at roomtemperature. The mixture was stirred under nitrogen atmosphere at 60° C.for 5 hr. To the mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was separated, washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (5.35 g). ¹H NMR (400 MHz, CDCl₃) δ 1.84 (1H, t, J=6.0 Hz),4.83 (2H, d, J=5.6 Hz), 7.08 (1H, tdd, J=8.4, 2.6, 1.1 Hz), 7.20-7.48(6H, m).

B) (2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl methanesulfonate

To a mixture of (2,3′-difluoro[1,1′-biphenyl]-3-yl)methanol (1.0 g) andTHF (20 ml) were added TEA (0.919 g) and methanesulfonic anhydride(0.949 g) at 0° C. The mixture was stirred at 0° C. for 30 min. To themixture was added saturated aqueous sodium hydrogencarbonate solution,and the mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to give thetitle compound (1.38 g). ¹H NMR (400 MHz, CDCl₃) δ 3.05 (3H, s), 5.36(2H, s), 7.05-7.15 (1H, m), 7.22-7.35 (3H, m), 7.38-7.55 (3H, m).

C)7-bromo-4-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-2H-quinolizine-3,6(1H,4H)-dione

A mixture of 7-bromo-2H-quinolizine-3,6(1H,4H)-dione (1.10 g),pyrrolidine (0.486 g) and toluene (20 ml) was refluxed for 2 hr. Thereaction solution was filtered through Celite, and the filtrate wasconcentrated under reduced pressure. A mixture of the obtained residue,(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl methanesulfonate (1.36 g),TBAI (0.337 g) and CH₃CN (30 ml) was stirred at 80° C. for 4 hr, and thereaction solution was concentrated. To the obtained residue was addedethyl acetate, and the mixture was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (519mg).

MS: [M+H]⁺444.0. D)3-bromo-6-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-7-(hydroxyimino)-6,7,8,9-tetrahydro-4H-quinolizin-4-one

To a mixture of7-bromo-4-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-2H-quinolizine-3,6(1H,4H)-dione(678 mg) and EtOH (6 ml) were added hydroxylamine hydrochloride (413 mg)and sodium acetate (611 mg) at room temperature. The reaction solutionwas refluxed for 30 min, and concentrated under reduced pressure. To theresidue was added ethyl acetate, and the mixture was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the title compound (0.69 g).

MS: [M+H]⁺459.1. E)rac-(6S,7S)-7-amino-3-bromo-6-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-6,7,8,9-tetrahydro-4H-quinolizin-4-one

To a mixture of3-bromo-6-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-7-(hydroxyimino)-6,7,8,9-tetrahydro-4H-quinolizin-4-one(0.69 g), molybdenum(6+) trioxide (0.324 g) and MeOH (65 ml) was addedsodium borohydride (0.682 g) at 0° C. The mixture was stirred at roomtemperature for 2 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the title compound (691 mg).

MS: [M+H]⁺445.1. F)(2S)-N-{(3SR,4SR)-7-bromo-4-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-5yl}oxolane-2-carboxamide

To a mixture ofrac-(6S,7S)-7-amino-3-bromo-6-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-6,7,8,9-tetrahydro-4H-quinolizin-4-one(360 mg) and DMF (5 ml) were added DIPEA (209 mg),(2S)-tetrahydrofuran-2-carboxylic acid (122 mg) and HATU (461 mg) atroom temperature. The mixture was stirred under nitrogen atmosphere atroom temperature for 3 hr. To the mixture was added saturated aqueoussodium hydrogencarbonate solution at room temperature, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane, and NH, ethylacetate/hexane) to give the title compound (327 mg).

MS: [M+H]⁺543.2. G)(2S)-N-{(3SR,4SR)-4-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide

A mixture of(2S)-N-{(3SR,4SR)-7-bromo-4-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide(80 mg), trimethylboroxin (55.4 mg),[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.8 mg),potassium carbonate (50.9 mg) and DME (5 ml) was irradiated withmicrowave at 110° C. for 1 hr. The impurities were removed byfiltration, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (68.3 mg).

MS: [M+H]⁺479.3. Example 52rac-N-[(7S,8R)-8-[([1,1′-biphenyl]-3-yl)methyl]-1-oxo-2-(propan-2-yl)-1,2,5,6,7,8-hexahydroisoquinolin-7-yl]methanesulfonamide A) 2-fluoro-4-iodo-3-(prop-2-en-1-yl)pyridine

To a mixture of 2-fluoro-3-iodopyridine (25.0 g) and THF (300 ml) wasadded dropwise 2M LDA THF/heptane solution (56.1 ml) under nitrogenatmosphere at −78° C. The mixture was stirred at −78° C. for 1 hr, andto the mixture was added allyl bromide (13.6 g) at −78° C. The mixturewas stirred under nitrogen atmosphere at 20° C. for 15 hr. To themixture was added saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/petroleumether) to give the title compound (25.7 g).

MS: [M+H]⁺263.8. B) 4-iodo-2-methoxy-3-(prop-2-en-1-yl)pyridine

To a mixture of 2-fluoro-4-iodo-3-(prop-2-en-1-yl)pyridine (25.7 g),MeOH (12.5 g) and THF (250 ml) was added 60% sodium hydride (7.03 g)little by little over 1 hr at 0° C. The mixture was stirred at 15° C.for 2 hr. To the mixture were added ice water and ethyl acetate, and themixture was warmed to room temperature, and extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give the title compound (29.0 g).

MS: [M+H]⁺275.8. C) methyl (4-iodo-2-methoxypyridin-3-yl)acetate

4-Iodo-2-methoxy-3-(prop-2-en-1-yl)pyridine (29.0 g) was dissolved indichloromethane (200 ml), and a mixture of sodium hydroxide (15.6 g) andMeOH (100 ml) was added thereto. The reaction solution was cooled to−78° C., and ozone was passed through the reaction solution for 30 min.Oxygen was passed through the reaction solution, and water and ethylacetate were added thereto, and the mixture was warmed to roomtemperature, and extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous io sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/petroleumether) to give the title compound (4.25 g).

MS: [M+H]⁺307.9. D) methyl3-([1,1′-biphenyl]-3-yl)-2-(4-iodo-2-methoxypyridin-3-yl)propanoate

To a mixture of methyl (4-iodo-2-methoxypyridin-3-yl)acetate (4.25 g),3-(bromomethyl)biphenyl (3.59 g), potassium iodide (4.59 g) and DMF (70ml) was added 1 M LHMDS THF solution (15.2 ml) under nitrogen atmosphereat −10° C. The mixture was warmed to 15° C., and stirred at 15° C. for14 hr. To the mixture was added saturated aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed with saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/petroleumether) to give the title compound (4.70 g).

MS: [M+H]⁺474.1. E) ethyl(2E)-3-{3-[3-([1,1′-biphenyl]-3-yl)-1-methoxy-1-oxopropan-2-yl]-2-methoxypyridin-4-yl}propa-2-enoate

A mixture of methyl3-([1,1′-biphenyl]-3-yl)-2-(4-iodo-2-methoxypyridin-3-yl)propanoate(4.70 g), ethyl acrylate (2.98 g), DIPEA (3.85 g), palladium(2+)diacetate (223 mg), tris(2-methylphenyl)phosphine (453 mg) and CH₃CN (80ml) was stirred under nitrogen atmosphere at 85° C. for 24 hr. Themixture was concentrated under reduced pressure, to the residue wasadded ethyl acetate, and the mixture was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (3.40 g).

MS: [M+H]⁺446.2. F) methyl3-([1,1′-biphenyl]-3-yl)-2-[4-(3-ethoxy-3-oxopropyl)-2-methoxypyridin-3-yl]propanoate

A mixture of ethyl(2E)-3-{3-[3-([1,1′-biphenyl]-3-yl)-1-methoxy-1-oxopropan-2-yl]-2-methoxypyridin-4-yl}propa-2-enoate(4.06 g), 10% palladium on carbon (400 mg) and MeOH (70 ml) was stirredunder normal hydrogen atmosphere at room temperature for 4 hr. Thecatalyst was removed by filtration, and the filtrate was concentratedunder reduced pressure to give the title compound (3.60 g).

MS: [M+H]⁺448.3. G)8-[([1,1′-biphenyl]-3-yl)methyl]-1-methoxy-5,8-dihydroisoquinolin-7(6H)-one

To a mixture of methyl3-([1,1′-biphenyl]-3-yl)-2-[4-(3-ethoxy-3-oxopropyl)-2-methoxypyridin-3-yl]propanoate(2.60 g) and THF (40 ml) was added 1 M potassium tert-butoxide THFsolution (6.4 ml) at 15° C. The mixture was stirred at 15° C. for 1 hr.The mixture was concentrated under reduced pressure, to the residue wasadded MeOH, and the mixture was again concentrated under reducedpressure. To the residue was added conc. hydrochloric acid (40 ml), andthe mixture was stirred under nitrogen atmosphere at 100° C. for 1 hr.The reaction solution was concentrated under reduced pressure, EtOH wasadded thereto, and the insoluble substance was removed by filtration.The filtrate was concentrated under reduced pressure to give the titlecompound (3.10 g).

MS: [M+H]⁺344.2. H)8-[([1,1′-biphenyl]-3-yl)methyl]-2,5,6,8-tetrahydroisoquinoline-1,7-dione

To a mixture of8-[([1,1′-biphenyl]-3-yl)methyl]-1-methoxy-5,8-dihydroisoquinolin-7(6H)-one(3.10 g), sodium iodide (2.61 g) and CH₃CN (45 ml) was added TMSCl (1.89g) at 0° C. The mixture was stirred at 50° C. for 3 hr. To the mixturewas added water at 0° C., and the mixture was extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (1.52 g).

MS: [M+Na]⁺352.2. I)8-[([1,1′-biphenyl]-3-yl)methyl]-7-(hydroxyimino)-5,6,7,8-tetrahydroisoquinolin-1(2H)-one

To a mixture of8-[([1,1′-biphenyl]-3-yl)methyl]-2,5,6,8-tetrahydroisoquinoline-1,7-dione(1.52 g) and EtOH (25 ml) were added hydroxylamine hydrochloride (603mg) and sodium acetate (979 mg) at room temperature. The reactionsolution was stirred at 80° C. for 2 hr, and concentrated under reducedpressure. To the residue was added ethyl acetate, and the mixture waswashed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give the titlecompound (1.65 g).

MS: [M+H]⁺345.2. J)rac-(7S,8R)-7-amino-8-[([1,1′-biphenyl]-3-yl)methyl]-5,6,7,8-tetrahydroisoquinolin-1(2H)-one

To a mixture of8-[([1,1′-biphenyl]-3-yl)methyl]-7-(hydroxyimino)-5,6,7,8-tetrahydroisoquinolin-1(2H)-one(1.65 g) and MeOH (65 ml) were added molybdenum(6+) trioxide (995 mg)and sodium borohydride (872 mg). The mixture was stirred under nitrogenatmosphere at room temperature for 2 hr. To the mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give the titlecompound (1.62 g).

MS: [M+Na]⁺353.2. K)rac-N-{(7S,8R)-8-[([1,1′-biphenyl]-3-yl)methyl]-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-7-yl}methanesulfonamide

To a mixture ofrac-(7S,8R)-7-amino-8-[([1,1′-biphenyl]-3-yl)methyl]-5,6,7,8-tetrahydroisoquinolin-1(2H)-one(1.62 g), TEA (1.87 g) and dichloromethane (25 ml) was addedmethanesulfonyl chloride (634 mg) at 0° C. The mixture was stirred undernitrogen atmosphere at 20° C. for 2 hr. To the mixture was added ethylacetate, and the mixture was washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was dissolved in THF (20 ml) and water (20 ml),and lithium hydroxide monohydrate (580 mg) was added thereto. Themixture was stirred at 50° C. for 14 hr. To the mixture was added ethylacetate, and the mixture was washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (810 mg).

MS: [M+H]⁺409.3. L)rac-N-[(7S,8R)-8-[([1,1′-biphenyl]-3-yl)methyl]-1-oxo-2-(propan-2-yl)-1,2,5,6,7,8-hexahydroisoquinolin-7-yl]methanesulfonamide

To a mixture ofrac-N-{(7S,8R)-8-[([1,1′-biphenyl]-3-yl)methyl]-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-7-yl}methanesulfonamide(80 mg), potassium carbonate (41 mg) and DMF (4 ml) was added2-iodopropane (33 mg) at 0° C. The mixture was stirred under nitrogenatmosphere at 20° C. for 14 hr. To the mixture was added 2-iodopropane(66 mg), and the mixture was again stirred at 20° C. for 14 hr. To themixture was added ethyl acetate, and the mixture was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified bypreparative HPLC, and freeze-dried to give the title compound (17 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.36 (6H, d, J=6.8 Hz), 2.00-2.15 (2H, m),2.46 (3H, s), 2.65-2.85 (3H, m), 3.20 (1H, d, J=14.8 Hz), 3.65-3.80 (2H,m), 4.29 (1H, d, J=8.0 Hz), 5.26-5.40 (1H, m), 6.04 (1H, d, J=6.8 Hz),7.20 (1H, d, J=6.8 Hz), 7.28-7.50 (5H, m), 7.51-7.63 (3H, m), 7.67 (1H,s).

Example 54(2S)-N-{(3S*,4S*)-4-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamidewith longer retention time

(2S)-N-{(3SR,4SR)-4-[(2,3′-Difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide(64.0 mg) was resolved by HPLC (column: CHIRALPAK ADH, 20 mmID×250 mmL(VA001), manufactured by Daicel Chemical Industries, mobile phase: EtOH)to give the title compound (27.4 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.14-1.33 (1H, m), 1.62-1.80 (4H, m), 1.87(1H, ddt, J=12.7, 7.8, 6.1 Hz), 1.98-2.13 (3H, m), 2.82-2.92 (1H, m),2.92-3.13 (2H, m), 3.29 (1H, dd, J=14.2, 10.0 Hz), 3.53-3.70 (3H, m),4.21-4.30 (1H, m), 5.52 (1H, dt, J=9.7, 3.6 Hz), 5.96 (1H, d, J=6.8 Hz),6.64 (1H, br d, J=8.3 Hz), 7.03-7.25 (3H, m), 7.27-7.44 (4H, m),7.75-7.81 (1H, m).

Example 99rel-N-[(5R,6S)-5-[([1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]methanesulfonamidewith longer retention time A)3′,5′,7′,8′-tetrahydro-4′H-spiro[1,3-dioxolane-2,6′-quinazoline]-4′-one

To a mixture of methyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate(68.6 g) and MeOH (640 ml) were added imidoformamide hydrochloride (38.7g) and 5 M sodium methanolate MeOH solution (160 ml) at roomtemperature. The mixture was stirred under argon atmosphere at 60° C.for 30 min. The mixture was allowed to cool to room temperature, andneutralized with 4 M hydrogen chloride/ethyl acetate solution. Silicagel was added thereto, and the mixture was concentrated under reducedpressure. The obtained residue was washed with a mixture of MeOH andethyl acetate (1:1), and the filtrate was concentrated under reducedpressure. The obtained solid was triturated with EtOH and IPE to givethe title compound (43.5 g).

MS: [M+H]⁺209.2. B)3′-(propan-2-yl)-3′,5′,7′,8′-tetrahydro-4′H-spiro[1,3-dioxolane-2,6′-quinazoline]-4′-one

To a mixture of3′,5′,7′,8′-tetrahydro-4′H-spiro[1,3-dioxolane-2,6′-quinazoline]-4′-one(20 g) and t-AmOH (480 ml) were added 2-iodopropane (82 g) andtripotassium phosphate (61.2 g) at room temperature. The mixture wasstirred overnight under argon atmosphere at 90° C. The mixture waspoured into water, and extracted with ethyl acetate. The organic layerwas separated, washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas triturated with IPE to give the title compound (11.5 g).

MS: [M+H]⁺251.2. C)3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione

To a mixture of3′-(propan-2-yl)-3′,5′,7′,8′-tetrahydro-4′H-spiro[1,3-dioxolane-2,6′-quinazoline]-4′-one(27.4 g) and THF (273 ml) was added 2 M hydrochloric acid (273 ml) atroom temperature. The mixture was stirred at 70° C. for 4 hr. Themixture was allowed to cool to room temperature, and concentrated underreduced pressure. To the residue was added saturated aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The organic layer was separated, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wastriturated with IPE to give the title compound (17.7 g).

MS: [M+H]⁺207.1. D)5-[([1,1′-biphenyl]-3-yl)methyl]-3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione

To a mixture of 3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione(1.5 g) and toluene (24.2 ml) was added pyrrolidine (2.07 g) at roomtemperature. The mixture was stirred under argon atmosphere at roomtemperature for 1 hr, and concentrated under reduced pressure. To amixture of the obtained residue and CH₃CN (24.2 ml) were added3-(bromomethyl)biphenyl (1.80 g) and TBAI (0.537 g) at room temperature.The mixture was stirred under argon atmosphere at 70° C. for 2 hr. Thereaction solution was allowed to cool to room temperature, andconcentrated under reduced pressure. To the residue were added ethylacetate and saturated aqueous ammonium chloride solution at roomtemperature, and the mixture was stirred for 1 hr. The mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (2.43 g).

MS: [M+H]⁺373.2. E)5-[([1,1′-biphenyl]-3-yl)methyl]-6-(hydroxyimino)-3-(propan-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

To a mixture of5-[([1,1′-biphenyl]-3-yl)methyl]-3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione(2.43 g) and EtOH (32.6 ml) were added hydroxylamine hydrochloride(0.499 g) and sodium acetate (0.696 g) at room temperature.

The mixture was stirred at 80° C. for 1 hr. The mixture was poured intowater, and extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to give the titlecompound (2.53 g).

MS: [M+H]⁺388.2. F)rac-(5R,6S)-6-amino-5-[([1,1′-biphenyl]-3-yl)methyl]-3-(propan-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

To a mixture of5-[([1,1′-biphenyl]-3-yl)methyl]-6-(hydroxyimino)-3-(propan-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one(2.53 g) and MeOH (32.6 ml) were added molybdenum(6+) trioxide (1.41 g)and sodium borohydride (1.23 g) at 0° C. The mixture was stirred at 0°C. for 1 hr. To the mixture was added saturated aqueous sodiumhydrogencarbonate solution at 0° C., and the mixture was extracted withethyl acetate. The organic layer was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (NH, MeOH/ethyl acetate/hexane) to give thetitle compound (1.36 g).

MS: [M+H]⁺374.3. G)rac-N-[(5R,6S)-5-[([1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]methanesulfonamide

To a mixture ofrac-(5R,6S)-6-amino-5-[([1,1′-biphenyl]-3-yl)methyl]-3-(propan-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one(195 mg) and THF (3 ml) were added TEA (106 mg) and methanesulfonicanhydride (109 mg) at 0° C. The mixture was stirred at 0° C. for 2 hr.To the mixture was added water, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (MeOH/ethyl acetate) to give the titlecompound (195 mg).

MS: [M+H]⁺452.3. H)rel-N-[(5R,6S)-5-[([1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]methanesulfonamidewith longer retention time

rac-N-[(5R,6S)-5-[([1,1′-Biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]methanesulfonamide(149 mg) was resolved by HPLC (column: CHIRALPAK IC (VB004), 20 mmID×250mmL, manufactured by Daicel

Chemical Industries, mobile phase: EtOH) to give the title compound(68.8 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.44 (6H, t, J=6.6 Hz), 2.06-2.19 (2H, m),2.51 (3H, s), 2.77-2.90 (3H, m), 3.14 (1H, dd, J=14.4, 2.7 Hz),3.63-3.71 (1H, m), 3.74-3.86 (1H, m), 4.26 (1H, d, J=8.6 Hz), 5.07 (1H,spt, J=6.8 Hz), 7.32-7.38 (1H, m), 7.39-7.49 (5H, m), 7.54-7.60 (2H, m),7.61 (1H, s), 8.05 (1H, s).

Example 156

rel-1-fluoro-N-[(5R,6S)-5-{[2-(2-fluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamidewith longer retention time

A)5-[(2-bromo-1,3-thiazol-4-yl)methyl]-3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione

To a mixture of 3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione(3.74 g) and toluene (60.5 ml) was added pyrrolidine (5.16 g) at roomtemperature. The mixture was stirred under argon atmosphere at roomtemperature for 30 min, and the reaction solution was concentrated. To amixture of the residue and CH₃CN (60.5 ml) were added2-bromo-4-(bromomethyl)-1,3-thiazole (4.66 g) and TBAI (1.34 g) at roomtemperature. The mixture was stirred under argon atmosphere at 70° C.for 1 hr. The mixture was allowed to cool to room temperature, and tothe mixture was added saturated aqueous ammonium chloride solution, andthe mixture was stirred overnight at room temperature. The mixture wasextracted with ethyl acetate, and the organic layer was separated,washed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (6.05 g).

MS: [M+H]⁺382.0. B)5-{[2-(2-fluorophenyl)-1,3-thiazol-4-yl]methyl}-3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione

To a mixture of5-[(2-bromo-1,3-thiazol-4-yl)methyl]-3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione(540 mg) and THF (14.1 mL) were added (2-fluorophenyl)boronic acid (395mg), XPhos Pd G3 (120 mg) and 1 M aqueous tripotassium phosphatesolution (4.24 ml) at room temperature. The mixture was stirred underargon atmosphere at 70° C. for 2 hr. To the mixture was added water atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (407 mg).

MS: [M+H]⁺398.1. C)rac-1-fluoro-N-[(5R,6S)-5-{[2-(2-fluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamide

To a mixture of5-{[2-(2-fluorophenyl)-1,3-thiazol-4-yl]methyl}-3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione(407 mg) and toluene (10.2 mL) were added1-fluorocyclopropane-1-sulfonamide (157 mg) and titanium(4+)tetraethanolate (701 mg) at room temperature. The mixture was stirredovernight under argon atmosphere at 100° C. To the mixture was addedsaturated aqueous sodium hydrogencarbonate solution at room temperature,and the mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. To a mixture of theobtained residue and MeOH (11.1 ml) was added sodium borohydride (126mg) at 0° C. The mixture was stirred under argon atmosphere at 0° C. for3 hr while adding sodium borohydride (126 mg) every 30 min. To themixture was added saturated aqueous sodium hydrogencarbonate solution at0° C., and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane,and NH, ethyl acetate/hexane) to give the title compound (128 mg).

MS: [M+H]⁺521.2. D)rel-1-fluoro-N-[(5R,6S)-5-{[2-(2-fluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamidewith longer retention time

rac-1-Fluoro-N-[(5R,6S)-5-{[2-(2-fluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamide(120 mg) was resolved by HPLC (column: CHIRALPAK IC (VB004), 20 mmID×250mmL, manufactured by Daicel Chemical Industries, mobile phase:hexane/EtOH=750/250) to give the title compound (40 mg). ¹H NMR (400MHz, DMSO-d₆) δ 1.24 (6H, dd, J=15.9, 6.8 Hz), 1.36-1.60 (4H, m),1.80-1.92 (1H, m), 1.94-2.12 (1H, m), 2.54-2.76 (2H, m), 2.87-2.97 (1H,m), 3.32-3.37 (1H, m), 3.47 (1H, br d, J=5.1 Hz), 3.64-3.77 (1H, m),4.59-4.73 (1H, m), 7.31 (1H, t, J=7.5 Hz), 7.34-7.42 (2H, m), 7.45-7.54(1H, m), 8.00-8.09 (1H, m), 8.27 (1H, s), 8.29-8.38 (1H, m).

Example 157

rac-1-fluoro-N-[(5R,6S)-5-{[2-(2-fluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2-yl)-1,2,3,4,5,6,7,8-octahydroquinazolin-6-yl]cyclopropane-1-sulfonamide

To a mixture of5-{[2-(2-fluorophenyl)-1,3-thiazol-4-yl]methyl}-3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione(407 mg) and toluene (10.2 mL) were added1-fluorocyclopropane-1-sulfonamide (157 mg) and titanium(4+)tetraethanolate (701 mg) at room temperature. The mixture was stirredovernight under argon atmosphere at 100° C. To the mixture was addedsaturated aqueous sodium hydrogencarbonate solution at room temperature,and the mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. To a mixture of theobtained residue and MeOH (11.1 ml) was added sodium borohydride (126mg) at 0° C. The mixture was stirred under argon atmosphere at 0° C. for3 hr while adding sodium borohydride (126 mg) every 30 min. To themixture was added saturated aqueous sodium hydrogencarbonate solution at0° C., and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane,and NH, ethyl acetate/hexane) to give the title compound (39 mg). ¹H NMR(400 MHz, DMSO-d₆) δ 0.76-0.81 (3H, m), 0.95-0.99 (3H, m), 1.36-1.56(4H, m), 1.68-1.81 (1H, m), 1.86-2.01 (1H, m), 35 2.21-2.37 (2H, m),2.69-2.78 (1H, m), 3.14-3.23 (1H, m), 3.32-3.35 (1H, m), 3.56-3.67 (1H,m), 3.93-4.00 (1H, m), 4.23-4.36 (2H, m), 6.42 (1H, br d, J=2.4 Hz),7.30 (3H, br d, J=2.0 Hz), 7.45-7.57 (1H, m), 8.17-8.30 (2H, m).

Example 172

N-[(5R,6S)-5-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropanesulfonamide

A)5-(3-bromo-2-fluorobenzyl)-3-isopropyl-3,5,7,8-tetrahydroquinazoline-4,6-dione

To a mixture of 3-(propan-2-yl)-3,5,7,8-tetrahydroquinazoline-4,6-dione(5.56 g) and toluene (200 mL) was added pyrrolidine (7.67 g) at roomtemperature. The mixture was stirred under nitrogen atmosphere at roomtemperature for 3 hr, and concentrated under reduced pressure. To amixture of the obtained residue and CH₃CN (150 mL) were added1-bromo-3-bromomethyl-2-fluorobenzene (7.80 g) and TBAI (0.996 g) atroom temperature. The mixture was stirred under nitrogen atmosphere at70° C. for 2.5 hr. The reaction solution was concentrated under reducedpressure, to the residue were added THF and saturated aqueous ammoniumchloride solution at room temperature, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (9.31 g).

MS: [M+H]⁺393.1. B)5-(3-bromo-2-fluorobenzyl)-6-(hydroxyimino)-3-isopropyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one

To a mixture of5-(3-bromo-2-fluorobenzyl)-3-isopropyl-3,5,7,8-tetrahydroquinazoline-4,6-dione(9.31 g) and EtOH (200 mL) were added hydroxylamine hydrochloride (6.58g) and sodium acetate (9.71 g) at room temperature. The mixture wasstirred under nitrogen atmosphere at 90° C. for 0.5 hr. The mixture wasconcentrated under reduced pressure, saturated brine was pouredthereinto at 0° C., and the mixture was extracted with ethyl acetate.The organic layer was separated, dried over anhydrous sodium sulfate,and concentrated under reduced pressure to give the title compound (10.6g).

MS: [M+H]⁺408.1. C)rac-(5R,6S)-6-amino-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one

To a mixture of5-(3-bromo-2-fluorobenzyl)-6-(hydroxyimino)-3-isopropyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one(10.6 g) and MeOH (150 mL) were added molybdenum(6+) trioxide (5.59 g)and sodium borohydride (2.94 g) at 0° C. The mixture was stirred undernitrogen atmosphere at room temperature for 4 hr. To the mixture wasadded saturated aqueous ammonium chloride solution at 0° C., and themixture was concentrated under reduced pressure to give the titlecompound (10.2 g).

MS: [M+H]⁺394.2. D) rac-tert-butyl((5R,6S)-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)carbamate

To a mixture ofrac-(5R,6S)-6-amino-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one(10.2 g), THF (100 mL) and water (100 mL) were added sodiumhydrogencarbonate (4.35 g) and di-t-butyl dicarbonate (11.9 mL) at roomtemperature. The mixture was stirred overnight under nitrogen atmosphereat room temperature. To the mixture was added water at 0° C., and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane), andthe obtained solid was washed with a mixed solvent of IPE/hexane to givethe title compound (6.05 g).

MS: [M+H]⁺494.2. E) tert-butyl((5R,6S)-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)carbamate

rac-tert-Butyl((5R,6S)-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)carbamate(3.71 g) was subjected to optical resolution by HPLC (column: CHIRALPAKIA (LA015), 20 mmID×250 mmL, manufactured by Daicel Chemical Industries,mobile phase: hexane/EtOH) to give the title compound with shorterretention time (1.67 g).

MS: [M+H]⁺494.2. F) tert-butyl[(5R,6S)-5-{[2,3′-difluoro-(1,1′-biphenyl)-3-yl]methyl}-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]carbamate

A mixture of tert-butyl((5R,6S)-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)carbamate(425 mg), (3-fluorophenyl)boronic acid (601 mg), 1 M aqueous potassiumphosphate solution (2.58 XPhos Pd G3 (21.8 mg) and THF (12 mL) wasirradiated with microwave at 80° C. for 40 min. The mixture wasextracted with ethyl acetate, and the organic layer was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (454mg).

MS: [M+H]⁺510.4. G)(5R,6S)-6-amino-5-{[2,3′-difluoro-(1,1′-biphenyl)-3-yl]methyl}-3-(propan-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

A mixture of tert-butyl[(5R,6S)-5-{[2,3′-difluoro-(1,1′-biphenyl)-3-yl]methyl}-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]carbamate(438 mg) and 10% hydrogen chloride/MeOH (20 mL) was stirred at roomtemperature for 12 hr. The mixture was concentrated under reducedpressure, to a mixture of the obtained residue and MeOH (20 mL) wasadded MP-carbonate, and the mixture was stirred at room temperature for2 hr. The MP-carbonate was removed by filtration, and the obtainedfiltrate was concentrated under reduced pressure to give the titlecompound (352 mg).

MS: [M+H]⁺410.3. H)N-[(5R,6S)-5-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropanesulfonamide

To a mixture of(5R,6S)-6-amino-5-{[2,3′-difluoro-(1,1′-biphenyl)-3-yl]methyl}-3-(propan-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one(103 mg) and THF (4 mL) were added TEA (0.473 mL) andcyclohexanesulfonyl chloride (0.095 mL) at room temperature. The mixturewas stirred at room temperature for 1 day, cyclohexanesulfonyl chloride(0.095 mL) was added 4 times at room temperature every 6 hr to 1 day,and 20 the mixture was stirred for 3 days in total. The mixture waspoured into water, and extracted with ethyl acetate. The organic layerwas separated, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (70.0 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 0.98 (4H, s), 1.08 (3H, d, J=6.6 Hz), 1.20(3H, d, J=6.8 Hz), 1.85-2.14 (2H, m), 2.52-2.65 (2H, m), 2.65-2.79 (2H,m), 3.18 (1H, dd, J=12.7, 5.1 Hz), 3.45-3.68 (2H, m), 4.45-4.57 (1H, m),7.05 (1H, t, J=8.6 Hz), 7.14-7.34 (5H, m), 7.43 (1H, d, J=6.6 Hz),7.46-7.54 (1H, m),8.24 (1H, s).

Example 176N-[(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropanesulfonamideA) tert-butyl ((5R,6S)-5-((2-fluoro-[1,1′-biphenyl]-3-5yl)methyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)carbamate

A mixture of tert-butyl((5R,6S)-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)carbamate(515 mg), phenylboronic acid (254 mg), XPhos Pd G3 (88 mg), 1M aqueouspotassium phosphate solution (3.13 mL) and THF (12 mL) was irradiatedwith microwave at 70° C. for 1 hr. To the mixture was added saturatedbrine at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (530 mg).

MS: [M+H]⁺492.3. B)(5R,6S)-6-amino-5-((2-fluoro-[1,1′-biphenyl]-3-yl)methyl)-3-isopropyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one

To a mixture of tert-butyl((5R,6S)-5-((2-fluoro-[1,1′-biphenyl]-3-yl)methyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)carbamate(0.53 g) and 5-10% hydrogen chloride/MeOH solution (5 mL) was added 4Mhydrogen chloride/CPME solution (10 mL) at 0° C., and the mixture wasstirred at room temperature for 30 min. The reaction solution wasconcentrated under reduced pressure, and the residue was diluted withMeOH. To the mixture was added MP-Carbonate at 0° C., and the mixturewas stirred under nitrogen atmosphere at room temperature for 3 hr. Theinsoluble substance was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give the title compound (457 mg).

MS: [M+H]⁺392.3. C)N-[(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropanesulfonamide

To a mixture of(5R,6S)-6-amino-5-((2-fluoro-[1,1′-biphenyl]-3-yl)methyl)-3-isopropyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one(90 mg) and THF (5 mL) were added TEA (0.096 mL) andcyclopropanesulfonyl chloride (0.047 mL) at 0° C. The mixture wasstirred overnight under nitrogen io atmosphere at room temperature. Tothe mixture was added saturated brine at 0° C., and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (51.3 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 0.87-1.02 (4H, m), 1.08 (3H, d, J=6.8 Hz),1.20 (3H, d, J=7.1 Hz), 1.90 (1H, d, J=8.8 Hz), 1.98-2.13 (1H, m),2.53-2.65 (2H, m), 2.68-2.75 (2H, m), 3.18 (1H, dd, J=13.2, 5.1 Hz),3.52-3.65 (2H, m), 4.50 (1H, quin, J=6.8 Hz), 7.00-7.07 (1H, m), 7.14(1H, t, J=6.5 Hz), 7.18-7.24 (1H, m), 7.33-7.46 (6H, m), 8.24 (1H, s).

Example 180

1-fluoro-N-[(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamide

A)N-((5R,6S)-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)-1-fluorocyclopropane-1-sulfonamide

To a mixture of5-(3-bromo-2-fluorobenzyl)-3-isopropyl-3,5,7,8-tetrahydroquinazoline-4,6-dione(5.9 g) and toluene (200 mL) were added1-fluorocyclopropane-1-sulfonamide (2.19 g) and titanium(4+)tetraethanolate (10.3 g) at room temperature. The mixture was stirredovernight under nitrogen atmosphere at 100° C. To the mixture was addedsaturated aqueous sodium hydrogencarbonate solution at room temperature,and the mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. To a mixture of theobtained residue and MeOH (150 mL) was added sodium borohydride (3.46 g)at 0° C. The mixture was stirred at 0° C. for 3 hr under nitrogenatmosphere while adding sodium borohydride (3.46 g) every 30 min. To themixture was added saturated aqueous sodium hydrogencarbonate solution at0° C., and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane,and NH, ethyl acetate/hexane) to give racemate of the title compound(4.48 g). The racemate was subjected to optical resolution by HPLC(column: CHIRALPAK IG(VJ003) 20 mmID*250 mmL, manufactured by DaicelChemical Industries, mobile phase: EtOH) to give the title compound withshorter retention time (1.61 g).

MS: [M+H]⁺516.2. B)1-fluoro-N-[(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamide

A mixture ofN-((5R,6S)-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)-1-fluorocyclopropane-1-sulfonamide(302 mg), phenylboronic acid (143 mg), XPhos Pd G3 (49.5 mg), 1M aqueouspotassium phosphate solution (1.75 mL) and THF (4 mL) was irradiatedwith microwave at 70° C. for 1 hr. The reaction solution was purified bysilica gel column chromatography (ethyl acetate/hexane), followed byHPLC (column: L-column2 ODS(CERI), 20 mmID×150 mmL, manufactured byChemicals Evaluation and Research Institute, mobile phase: aqueousammonium bicarbonate solution/MeCN) to give the title compound (210 mg).

MS: [M+H]⁺514.3.

¹H NMR (300 MHz, DMSO-d₆) δ 1.07 (3H, d, J=6.8 Hz), 1.19 (3H, d, J=7.2Hz), 1.34-1.62 (4H, m), 1.84-1.96 (1H, m), 2.07-2.28 (1H, m), 2.57 (1H,dd, J=12.8, 10.2 Hz), 2.66-2.81 (2H, m), 3.21 (1H, dd, J=13.4, 4.7 Hz),3.52-3.72 (2H, m), 4.47 (1H, quin, J=6.8 Hz), 7.00-7.24 (3H, m),7.33-7.48 (5H, m), 8.22 (1H, s), 8.31 (1H, brs).

Example 195

N-{(5R,6S)-4-oxo-3-(propan-2-yl)-5-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin-6-yl}cyclopropanesulfonamide

A)(5R,6S)-6-amino-5-(3-bromo-2-fluorobenzyl)-3-(propan-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

A mixture of tert-butyl((5R,6S)-5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6-yl)carbamate(710 mg) and 10% hydrogen chloride/MeOH (30 mL) was stirred overnight atroom temperature. The mixture was concentrated under reduced pressure,to a mixture of the obtained residue and MeOH (40 ml) was addedMP-carbonate, and the mixture was stirred for 3 hr. The MP-carbonate wasremoved by filtration, and the obtained filtrate was concentrated underreduced pressure to give the title compound (550 mg).

MS: [M+H]⁺394.1. B)N-[(5R,6S)-5-(3-bromo-2-fluorobenzyl)-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropanesulfonamide

To a mixture of(5R,6S)-6-amino-5-(3-bromo-2-fluorobenzyl)-3-(propan-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one(550 mg), TEA (1.94 mL), DMAP (0.341 g) and THF (20 mL) was addedcyclohexanesulfonyl chloride (0.568 mL) at 0° C. The mixture was stirredfor 8 hr, and cyclohexanesulfonyl chloride (0.568 mL) was added thereto.The mixture was stirred for additional 1 day, cyclohexanesulfonylchloride (0.568 mL) was added thereto, and the mixture was stirred foradditional 1 day. To the mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was separated, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.340 g).

MS: [M+H]⁺498.1. C)N-{(5R,6S)-4-oxo-3-(propan-2-yl)-5-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin-6-yl}cyclopropanesulfonamide

A mixture ofN-[(5R,6S)-5-(3-bromo-2-fluorobenzyl)-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropanesulfonamide(340 mg), (3,5-difluorophenyl)boronic acid (539 mg), 1M aqueouspotassium phosphate solution (2.05 mL), XPhos Pd G3 (17.3 mg) and THF(10 mL) was irradiated with microwave at 80° C. for 40 min. The mixturewas extracted with ethyl acetate, and the organic layer was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane), and the obtained solid wasrecrystallized from IPE/hexane to give the title compound (280 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 0.82-1.04 (4H, m), 1.10 (2H, d, J=6.8 Hz),1.20 (3H, d, J=6.8 Hz), 1.23-1.29 (1H, m), 1.85-2.17 (2H, m), 2.52-2.78(4H, m), 3.18 (1H, dd, J=13.2, 6.4 Hz), 3.49-3.67 (2H, m), 4.45-4.60(1H, m), 7.07 (1H, t, J=7.6 Hz), 7.14-7.34 (5H, m), 7.35-7.43 (1H, m),8.23 (1H, s).

The compounds of Examples are shown in the following tables. MS in thetables means actual measured value. The compounds of Examples 2 to 4, 7to 9, 11 to 23, 25 to 49, 51, 35 53, 55 to 98, 100 to 155, 158 to 171,173 to 175, 177 to 179, 181 to 194 and 196 to 216 in the followingtables were produced according to the methods described in theabove-mentioned Examples, or methods analogous thereto.

TABLE 1 Ex. No. IUPAC Name Structure MS 1 rac-N-{(3S,4S)-4-[([1,1′-biphenyl]-3-yl)methyl]-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

407.2 2 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6,7,8-hexahydro-2H- quinolizin-3- yl}methanesulfonamide

411.3 3 rac-N-{(3S,4S,9aS)-4-[([1,1′- biphenyl]-3-yl)methyl]-6-oxooctahydro-2H-quinolizin-3- yl}methanesulfonamide

413.3 4 rac-N-{(3S,4S,9aR)-4-[([1,1′- biphenyl]-3-yl)methyl]-6-oxooctahydro-2H-quinolizin-3- yl}methanesulfonamide

413.3 5 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-bromo-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

487.0 6 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

423.2 7 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-9-bromo-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

486.8 8 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-9-methyl-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

423.0 9 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-bromo-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}ethanesulfonamide

501.1 10 rel-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide withshorter retention time obtained by HPLC (column: CHIRALPAK ID, mobilephase: hexane/2 propanol = 200/800)

423.3 11 rac-N-{(3S,4S)-4-[([(1,1′- biphenyl]-3-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}ethanesulfonamide

437.2 12 rac-N-[(3S,4S)-4-[([1,1′- biphenyl]-3-yl]methyl-6-oxo-7-(trifluoromethyl)-1,3,4,6- tetrahydro-2H-quinolizin-3-yl]methanesulfonamide

477.1 13 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7,9-dimethyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

437.1 14 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-8-methyl-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

423.3 15 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-chloro-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

443.1 16 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-fluoro-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

427.1 17 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-9-fluoro-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

427.2 18 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-bromo-8-methyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

501.0 19 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7,8-dimethyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

437.2 20 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-8,9-dimethyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

437.2 21 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-9-fluoro-7-methyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

441.3 22 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-cyclopropyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

449.2 23 (2S)-N-{(3SR,4SR)-7-bromo-4- [(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide

525.1 25 (2S)-N-{(3SR,4SR)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-bromo-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3-yl}oxolane-2- carboxamide

507.1 26 (2S)-N-{(3SR,4SR)-4-[(3′- fluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide

461.3 27 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-ethyl-6-oxo-1,3,4,6-tetrahydro-2H- quinozilin-3- yl}methanesulfonamide

437.3 28 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-cyano-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

434.2 29 (2S)-N-{(3SR,4SR)-4-[(3′- fluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6- oxooctahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide

465.3 30 rac-methyl (3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-3-[(methanesulfonyl)amino]-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizine-7-carboxylate

467.2 31 rac-N-[(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-(dimethylamino)-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl]methanesulfonamide

452.2 32 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-9-chloro-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

443.2 33 rac-N-[(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-(2-hydroxypropan-2-yl)-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide

465.1 34 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-7-methoxy-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3- yl}methanesulfonamide

439.2 35 rac-N-{(1S,3S,4S)-4-[([1,1′- biphenyl]-3-yl)methyl]-1-methoxy-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3- yl}methanesulfonamide

439.3 36 rac-N~2~-{(3S,4S)-7-bromo-4- [(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}- N~1~,N~1~-dimethylethanediamide

544.0 37 rac-N~2~-{(3S,4S)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}-N~1~,N~1~- dimethylethanediamide

480.2 38 rac-N~2~-{(3S,4S)-7- cyclopropyl-4-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}-N~1~,N~1~- dimethylethanediamide

506.3 39 rac-N~2~-{(3S,4S)-4-[2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-ethyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}-N~1~,N~1~- dimethylethanediamide

494.2 40 rac-N~2~-[(3S,4S)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo-7-(propan-2- yl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]-N~1~,N~1~- dimethylethanediamide

508.3 41 rac-N-{(5S,6S,8aS)-5-[([1,1′- biphenyl]-3-yl)methyl]-2-methyl-3-oxooctahydroimidazo[1,5- a]pyridin-6- yl}methanesulfonamide

414.3 42 rel-N~2~-{(3S,4S)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-ethyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}-N~1~,N~1~- dimethylethanediamide with shorter retention time obtained byHPLC (column: CHIRALPAK ADH, mobile phase: EtOH)

494.3 43 rel-N~2~-{(3S,4S)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-ethyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}-N~1~,N~1~- dimethylethanediamide with longer retention time obtained byHPLC (column: CHIRALPAK ADH, mobile phase: EtOH)

494.3 44 (2S)-N-{(3S*,4S*)-4-[(3′- fluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide with longer retention time obtained by HPLC(column: CHIRALPAK ADH, mobile phase: EtOH)

461.3 45 rac-N-{(7S,8R)-8-[([1,1′- biphenyl]-3-yl)methyl]-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 7-yl}methanesulfonamide

409.2 46 rac-N-{(7S,8R)-8-[([1,1′- biphenyl]-3-yl)methyl]-2-methyl-1-oxo-1,2,5,6,7,8- hexahydroisoquinolin-7- yl}methanesulfonamide

423.3 47 rac-N-{(7S,8R)-8-[([1,1′- biphenyl]-3-yl)methyl]-2-ethyl-1-oxo-1,2,5,6,7,8- hexahydroisoquinolin-7- yl}methanesulfonamide

437.2 48 (2S)-N-{(3SR,4SR)-7-bromo-4- [(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide

543.1 49 rac-N-{(3S,4S)-7-bromo-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}-1-methoxycyclopropane-1- carboxamide

543.1 50 (2S)-N-{(3SR,4SR)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide

479.2 51 rac-N-{(3S,4S)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}-1-methoxycyclopropane-1- carboxamide

479.3 52 rac-N-[(7S,8R)-8-[([1,1′- biphenyl-3-yl)methyl]-1-oxo-2-(propan-2-yl)-1,2,5,6,7,8- hexahydroisoquinolin-7- yl]methanesulfonamide

451.3 53 (2S)-N-{(3S*,4S*)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide with shorter retention time obtained by HPLC(column: CHIRALPAK ADH, mobile phase: EtOH)

479.3 54 (2S)-N-{(3S*,4S*)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}oxolane-2-carboxamide with longer retention time obtained by HPLC(column: CHIRALPAK ADH, mobile phase: EtOH)

479.3 55 rel-N-{(3S,4S)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}-1-methoxycyclopropane-1- carboxamide with shorter retention timeobtained by HPLC (column: CHIRALPAK ADH, mobile phase: hexane/EtOH)

479.2 56 rel-N-{(3S,4S)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}-1-methoxycyclopropane-1- carboxamide with longer retention timeobtained by HPLC (column: CHIRALPAK ADH, mobile phase: hexane/EtOH)

479.3 57 rac-N-{(3S,4S)-7-methyl-6-oxo-4-[(6-phenylpyridin-2-yl)methyl]- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

424.3 58 rac-N-{(3S,4S)-7-methyl-6-oxo- 4-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

430.2 59 rac-N-[(3S,4S)-4-{[6-(3- fluorophenyl)pyridin-2-yl]methyl}-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide

442.2 60 rac-N-[(3S,4S)-4-{[6-(3,5- difluorophenyl)pyridin-2-yl]methyl}-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide

460.2 61 rac-N-{(6S,7S)-6-[([1,1′- biphenyl]-3-yl)methyl]-1,3-dichloro-4-oxo-6,7,8,9-tetrahydro- 4H-pyrido[1,2-a]pyrazin-7-yl}methanesulfonamide

478.1 62 rac-N-{(4aS,7S,8S)-8-[([1,1′- biphenyl]-3-yl)methyl]-2-methyl-1-oxooctahydro-1H-pyrido[1,2- c]pyrimidin-7- yl}methanesulfonamide

428.3 63 rac-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]-1-methoxycyclopropane-1- carboxamide

472.3 64 rac-N-[(3S,4S)-4-{[2-(3- fluorophenyl)-1,3-thiazol-4-yl]methyl}-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide

448.2 65 rac-N-[(3S,4S)-4-{[2-(3,5- difluorophenyl)-1,3-thiazol-4-yl]methyl}-7-methyl-6-oxo- 1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide

466.1 66 rac-N-[(5R,6S)-5-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]methanesulfonamide

470.2 67 rac-N-[(5R,6S)-5-[(3′,5′- difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

488.3 68 rel-N-{(3S,4S)-4-[(3′-fluoro[1,1′-biphenyl-3-yl)methyl]-7-methyl- 6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3- yl}methanesulfonamide with shorter retention time obtainedby HPLC (column: CHIRALPAK IC, mobile phase: EtOH)

441.2 69 rel-N-{(3S,4S)-4-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-7-methyl- 6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3- yl}methanesulfonamide with longer retention time obtainedby HPLC (column: CHIRALPAK IC, mobile phase: EtOH)

441.2 70 rac-N-{(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-2-methyl-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl}methanesulfonamide

466.3 71 rac-N-{(5R,6S)-5-[([1,1′- biphenyl]-3-methyl]-3-ethyl-2-methyl-4-oxo-3,4,5,6,7,8- hexahydroquinazolin-6- yl}methanesulfonamide

452.3 72 rac-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-2-methyl-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]-1-methoxycyclopropane-1- carboxamide

486.4 73 rac-N-[(5R,6S)-5-[(3′,4′- difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

488.3 74 rac-N-[(7S,8R)-8-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-1-oxo-2- (propan-2-yl)-1,2,5,6,7,8-hexahydroisoquinolin-7- yl]methanesulfonamide

469.3 75 rac-N-{(5R,6S)-5-[(3′,5′- difluoro[1,1′-biphenyl]-3-yl)methyl]-3-methyl-2-methyl-4- oxo-3,4,5,6,7,8- hexahydroquinazolin-6-yl}methanesulfonamide

488.3 76 rac-N-{(5R,6S)-3-ethyl-5-[(3′- fluoro[1,1′-biphenyl]-3-yl)methyl]-2-methyl-4-oxo- 3,4,5,6,7,8-hexahydroquinazolin-6-yl}methanesulfonamide

470.3 77 rac-N-{(5R,6S)-3-ethyl-5-[(2′- fluoro[1,1′-biphenyl]-3-yl)methyl]-2-methyl-4-oxo- 3,4,5,6,7,8-hexahydroquinazolin-6-yl}methanesulfonamide

470.3 78 rac-N-{(5R,6S)-3-ethyl-2-methyl-5-[(3′-methyl[1,1′-biphenyl]-3- yl)methyl]-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6- yl}methanesulfonamide

466.3 79 rac-N-{(7S,8R)-2-ethyl-8-[(3′- fluoro[1,1′-biphenyl]-3-yl)methyl]-1-oxo-1,2,5,6,7,8- hexahydroisoquinolin-7-yl}methanesulfonamide

455.2 80 rac-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6- yl]ethanesulfonamide

466.3 81 rac-N-[(5R,6S)-5-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]ethanesulfonamide

484.3 82 rac-N-[(5R,6S)-5-[(3′-chloro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]ethanesulfonamide

500.2 83 rac-N-[(5R,6S)-5-[(2′-fluoro-3′- methyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]ethanesulfonamide

498.2 84 rac-N-[(5R,6S)-5-[(2′-fluoro-5′- methyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]ethanesulfonamide

498.2 85 rac-N-[(5R,6S)-5-[(2′,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]ethanesulfonamide

502.3 86 rac-N-[(5R,6S)-5-[(2′,5′- difluoro[1,1′-bipheny]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroisoquinolin-6-yl]ethanesulfonamide

502.2 87 rac-N-{(7S,8R)-2-ethyl-8-[(2- fluoro[1,1′-biphenyl]-3-yl)methyl]-1-oxo-1,2,5,6,7,8- hexahydroisoquinolin-7-yl}methanesulfonamide

455.2 88 rac-N-[(5R,6S)-5-[(2′-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]ethanesulfonamide

484.2 89 rel-N-[(5R,6S)-5-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroisoquinazolin-6- yl]methanesulfonamide with shorter retentiontime obtained by HPLC (column: CHIRALPAK ADH, mobile phase: hexane/EtOH)

470.2 90 rel-N-[(5R,6S)-5-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroisoquinazolin-6- yl]methanesulfonamide with longer retentiontime obtained by HPLC (column: CHIRALPAK ADH, mobile phase: hexane/EtOH)

470.2 91 rel-N-[(5R,6R)-5-[(3′,5′- difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide with longer retention time obtained by HPLC(column: CHIRALPAK IC, mobile phase: EtOH)

488.2 92 rac-N-{(7S,8R)-8-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-2-ethyl-1-oxo- 1,2,5,6,7,8-hexahydroisoquinolin-7-yl}methanesulfonamide

473.2 93 rac-N-{(7S,8R)-2-ethyl-8-[(2-fluoro-3′-methyl[1,1′-biphenyl]-3- yl)methyl]-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-7- yl}methanesulfonamide

469.2 94 rac-N-{(6S,7S)-6-[([1,1′- biphenyl]-3-yl)methyl]-3-methyl-4-oxo-6,7,8,9-tetrahydro-4H- pyrido[1,2-a]pyrimidin-7-yl}methanesulfonamide

424.2 95 rac-N-{(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-2,3-dimethyl-4-oxo-3,4,5,6,7,8- hexahydroquinazolin-6- yl}methanesulfonamide

438.2 96 rac-N-{(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-1,3-dimethyl-4-oxo-3,4,5,6,7,8- hexahydrophthalazin-6- yl}methanesulfonamide

438.3 97 rac-N-{(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-1,3-dimethyl-4-oxo-3,4,5,6,7,8- hexahydrophthlalazin-6- yl}ethanesulfonamide

452.2 98 rac-N-[(5R,6S)-5-{[3-(4- methylpyridin-2-yl)phenyl]methyl}-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]ethanesulfonamide

481.3 99 rel-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6- yl]methanesulfonamidewith longer retention time obtained by HPLC (column: CHIRALPAK IC,mobile phase: EtOH)

452.2 100 rel-N-[(5R,6S)-5-[(3′-methyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]ethanesulfonamide with longer retention timeobtained by HPLC (column: CHIRALPAK IC, mobile phase: EtOH)

480.3 101 rac-N-{(3S,4S)-4-[(3′,5′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-ethyl-6-oxo-1,3,4,6- tetrahydro-2H-quinozilin-3-yl}methanesulfonamide

473.2 102 rac-N-[(5R,6S)-5-{[3-(4,6- dimethylpyridin-2-yl)phenyl]methyl}-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]ethanesulfonamide

495.3 103 rac-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-3-(cyclopropylmethyl)-4-oxo- 3,4,5,6,7,8-hexahydroquinazolin-6-yl]methanesulfonamide

464.2 104 rac-N-{(3S,4S)-7-ethyl-4-[(2- fluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

455.2 105 rac-N-{(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-3-cyclopropyl-4-oxo-3,4,5,6,7,8- hexahydroquinazolin-6-yl}methanesulfonamide

450.2 106 rac-N-[(5R,6S)-5-[(3′- methyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

466.2 107 rac-N-[(5R,6S)-5-[(2′-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]methanesulfonamide

470.2 108 rac-N-[(5R,6S)-5-[(2′-fluoro-3′- methyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

484.2 109 rac-N-[(5R,6S)-5-[(3′-fluoro-5′- methyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

484.3 110 rac-N-[(5R,6S)-5-[(2′-fluoro-5′- methyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

484.2 111 rac-N-[(5R,6S)-5-[(3′,5′- dimethyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

480.3 112 rac-N-[(5R,6S)-5-[(2′,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

488.2 113 rac-N-[(5R,6S)-5-[(2′-fluoro-3′- methoxy[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

500.2 114 rac-N-[(5R,6S)-5-{[3-(2,3- dihydro-1-benzofuran-7-yl)phenyl]methyl}-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]methanesulfonamide

494.2 115 rac-N-[(5R,6S)-5-[2′,5′-difluoro- 3′-methyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

502.2 116 rac-N-[(5R,6S)-5-[(2′,3′-difluoro- 5′-methyl[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

502.2 117 rac-N-[(5R,6S)-5-{[3-(1-methyl-1H-pyrazol-3-yl)phenyl]-methyl}- 4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]methanesulfonamide

456.3 118 rac-N-{(7S,8R)-2-ethyl-8-[(3′- methyl[1,1′-biphenyl]-3-yl)methyl]-1-oxo-1,2,5,6,7,8- hexahydroisoquinolin-7-yl}methanesulfonamide

451.3 119 rac-N-{(7S,8R)-2-ethyl-8-[(2′- fluoro[1,1′-biphenyl]-3-yl)methyl]-1-oxo-1,2,5,6,7,8- hexahydroisoquinolin-7-yl}methanesulfonamide

455.2 120 rac-N-{(7S,8R)-2-ethyl-8-[(2′-fluoro-3′-methyl[1,1′-biphenyl]-3- yl)methyl]-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-7- yl}methanesulfonamide

469.2 121 rac-N-{(7S,8R)-2-ethyl-8-[(3′-fluoro-5′-methyl[1,1′-biphenyl]-3- yl)methyl]-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-7- yl}methanesulfonamide

469.2 122 rac-N-{(7S,8R)-2-ethyl-8-[(2′-fluoro-5′-methyl[1,1′-biphenyl]-3- yl)methyl]-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-7- yl}methanesulfonamide

469.2 123 rac-N-{(7S,8R)-8-[(3′,5′- dimethyl[1,1′-biphenyl]-3-yl)methyl]-2-ethyl-1-oxo- 1,2,5,6,7,8-hexahydroisoquinolin-7-yl}methanesulfonamide

465.2 124 rac-N-{(7S,8R)-8-[(2′,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-2-ethyl-1-oxo- 1,2,5,6,7,8-hexahydroisoquinolin-7-yl}methanesulfonamide

473.2 125 rac-N-{(7S,8R)-2-ethyl-8-[(2′-fluoro-3′-methoxy[1,1′-biphenyl]- 3-yl)methyl]-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-7- yl}methanesulfonamide

485.2 126 rac-N-[(7S,8R)-8-{[3-(2,3- dihydro-1-benzofuran-7-yl)phenyl]methyl}-2-ethyl-1-oxo- 1,2,5,6,7,8-hexahydroisoquinolin-7-yl]methanesulfonamide

479.2 127 rac-N-{(7S,8R)-8-[(2′,5′-difluoro- 3′-methyl[1,1′-biphenyl]-3-yl)methyl]-2-ethyl-1-oxo- 1,2,5,6,7,8-hexahydroisoquinolin-7-yl}methanesulfonamide

487.2 128 rac-N-{(7S,8R)-8-[(2′,3′-difluoro- 5′-methyl[1,1′-biphenyl]-3-yl)methyl]-2-ethyl-1-oxo- 1,2,5,6,7,8-hexahydroisoquinolin-7-yl}methanesulfonamide

487.2 129 rac-N-[(7S,8R)-2-ethyl-8-{[3-(1-methyl-2-oxo-1,2-dihydropyridin- 3-yl)phenyl]methyl}-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 7-yl]methanesulfonamide

468.3 130 rac-N-[(5R,6S)-5-{[3- (benzyloxy)phenyl]methyl}-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroisoquinazolin-6-yl]methanesulfonamide

482.3 131 rac-N-{(3S,4S)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-7-ethyl-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

473.2 132 rac-N-{[3S,4S)-7-ethyl-6-oxo-4-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3- yl)methyl]-1,3,4,6-tetrahydro-2H-quinolizin-3- yl}methanesulfonamide

491.1 133 rac-N-[(5R,6S)-4-oxo-5-[(2- phenoxyphenyl)methyl]-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6- yl]methanesulfonamide

468.3 134 rac-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]cyclopropanesulfonamide

478.2 135 rac-N-{(3S,4S)-7-ethyl-4-[(3- ethylphenyl)methyl]-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin- 3-yl}methanesulfonamide

389.3 136 rac-N-{(3S,4S)-4-[(3- cyclopropylphenyl)methyl]-7-ethyl-6-oxo-1,3,4,6-tetrahydro- 2H-quinolizin-3- yl}methanesulfonamide

401.3 137 rac-N-{(3S,4S)-7-ethyl-4-[(3′- fluoro[1,1′-biphenyl]-3-yl)methyl]-6-oxo-1,3,4,6- tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

455.2 138 rac-N-{(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-1-methyl-4-oxo-3,4,5,6,7,8- hexahydrophthalazin-6- yl}methanesulfonamide

424.3 139 rel-N-[(5S,6R)-5-[([1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]-1,1-difluoromethanesulfonamide with longer retention time obtained by HPLC(column: CHIRALPAK IC, mobile phase: hexane/2- propanol)

488.2 140 rel-N-{(6S,7S,9aS)-6-[(3′- fluoro[1,1′-biphenyl]-3-yl)methyl]-3-methyl-4- oxooctahydropyrido[2,1- c][1,4]oxazin-7-yl}methanesulfonamide with longer retention time obtained by HPLC(column: Xbridge, mobile phase: 0.05% NH3H2O/CH3CN), which was derivedfrom rel-tert- butyl-N-{(6S,7S,9aS)-6-[[3-(3-fluorophenyl)-phenyl]methyl]-3- methyl-4-oxo-1,6,7,8,9,9a-hexahydropyrido[2,1- c][1,4]oxazin-7-yl}carbamate with shorter retentiontime obtained by SFC (column: CHIRALCEL OJ-3,

447.3 mobile phase: carbon dioxide/0.05% diethylamine in EtOH) 141rel-N-[(5R,6S)-5-[(5-fluoro[1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6- yl]methanesulfonamidewith longer retention time obtained by SFC (column: CHIRALPAK AD, mobilephase: carbon dioxide/0.05% diethylamine in MeOH)

470.2 142 rel-N-[(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]methanesulfonamide with shorter retention timeobtained by SFC (column: CHIRALCEL OJ-3, mobile phase: carbondioxide/0.05% diethylamine in MeOH)

470.2 143 rac-N-{(7S,8R)-8-[([1,1′- biphenyl]-3-yl)methyl]-2-ethyl-4-fluoro-1-oxo-1,2,5,6,7,8- hexahydroisoquinolin-7- yl}methanesulfonamide

455.2 144 rac-N-[(5R,6S)-5-{[2-(2- fluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

477.2 145 rel-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]-1-fluoromethanesulfonamide with longer retention time obtained by HPLC(column: CHIRALPAK IC, mobile phase: hexane/2- propanol)

470.2 146 rac-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]-1-fluorocyclopropane-1- sulfonamide

496.2 147 rac-N-{(7S,8R)-8-[(2′,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-2-(~2~H_5_)ethyl-1- oxo-1,2,5,6,7,8- hexahydroisoquinolin-7-yl}methanesulfonamide

478.3 148 rac-N-[(7S,8R)-1-oxo-8-[(6- phenylpyridin-2-yl)methyl]-2-(propan-2-yl)-1,2,5,6,7,8- hexahydroisoquinolin-7- yl]methanesulfonamide

452.3 149 rel-N-[(5R,6S)-5-[(2,2′- difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide, which was derived from rel-N-((5S,6R)-5-(3-bromo-2-fluorobenzyl)-3- isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6- yl)methanesulfonamide with longer retention timeobtained by SFC (column: CHIRALPAK IC-3, mobile phase: carbondioxide/0.05% diethylamine in MeOH)

488.2 150 rel-N-[(5R,6S)-5-[(6-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]methanesulfonamide with longer retention timeobtained by SFC (column: Amycoat, mobile phase: carbon dioxide/0.05%diethylamine in MeOH)

470.2 151 rel-N-{(5R,6S)-4-oxo-3-(propan-2-yl)-5-[(2,2′,3′-trifluoro[1,1′- biphenyl]-3-yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin- 6-yl}methanesulfonamide, which wasderived from rel-N-((5S,6R)- 5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8- hexahydroquinazolin-6-yl)methanesulfonamide with longer retained time obtained by SFC (column:CHIRALPAK IC-3, mobile phase: carbon dioxide/0.05% diethylamine in MeOH)

506.2 152 rel-N-[(5R,6S)-5-{[3′- (difluoromethyl)-2,2′-difluoro[1,1′-biphenyl]-3-yl]methyl}-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]methanesulfonamide, which was derived fromrel-N-((5S,6R)- 5-(3-bromo-2-fluorobenzyl)-3-isopropyl-4-oxo-3,4,5,6,7,8- hexahydroquinazolin-6-yl)methanesulfonamide with longer retained time obtained by SFC (column:CHIRALPAK IC-3, mobile phase: carbon dioxide/0.05% diethylamine in MeOH)

538.1 153 rac-N-[(7S,8R)-8-{[2-(3,5- difluorophenyl)-1,3-thiazol-4-yl]methyl}-2-ethyl-1-oxo- 1,2,5,6,7,8-hexahydroisoquinolin-7-yl]methanesulfonamide

480.2 154 rel-N-[(5R,6S)-5-{[2-(2,3- difluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide with longer retention time obtained by HPLC(column: CHIRALPAK IC, mobile phase: EtOH)

495.1 155 rel-N-[(5R,6S)-5-{[2-(2- fluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide with longer retention time obtained by HPLC(column: CHIRALPAK IC, mobile phase: EtOH)

477.2 156 rel-1-fluoro-N-[(5R,6S)-{[2-(2- fluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamide with longer retention time obtained byHPLC (column: CHIRALPAK IC, mobile phase: hexane/EtOH = 750/250)

521.2 157 rel-1-fluoro-N-[(5R,6S)-5-{[2-(2- fluorophenyl)-1,3-thiazol-4-yl]methyl}-4-oxo-3-(propan-2- yl)-1,2,3,4,5,6,7,8-octahydroquinazolin-6- yl]cyclopropane-1-sulfonamide

523.2 158 rac-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-1-methyl-4-oxo-3-(propan-2-yl)-1,4,5,6,7,8- hexahydrocinnolin-6-yl]methanesulfonamide

466.3 159 rel-N-[(5R,6S)-5-[(2′-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]methanesulfonamide, which was derived fromrel-N-((5S,6R)- 5-(3-bromobenzyl)-3-isopropyl-4- oxo-3,4,5,6,7,8-hexahydroquinazolin-6- yl)methanesulfonamide with longer retention timeobtained by SFC (column: CHIRALPAK IC-3, mobile phase: carbondioxide/0.05% diethylamine in MeOH)

470.2 160 rac-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-1,2,3,4,5,6,7,8- octahydroquinazolin-6-yl]cyclopropanesulfonamide

480.2 161 rel-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-1-methyl-4-oxo-3-(propan-2-yl)-1,4,5,6,7,8- hexahydrocinnolin-6-yl]methanesulfonamide with longer retention time obtained by HPLC(column: CHIRALPAK IC, mobile phase: hexane/2- propanol)

466.5 162 rac-N-[(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-8,8-difluoro-4-oxo-3-(propan-2-yl)- 1,2,3,4,5,6,7,8- octahydroquinazolin-6-yl]methanesulfonamide

490.2 163 rac-N-{(7S,8R)-2-ethyl-8-[(2- fluoro[1,1′-biphenyl]-3-yl)methyl]-1,5-dioxo-1,2,5,6,7,8- hexahydroisoquinolin-7-yl}methanesulfonamide

469.0 164 rel-N-[(5R,6S)-5-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide, which was derived from rel-N-((5S,6R)-5-(3-bromo-2-fluorobenzyl)-3- isopropyl-4-oxo-3,4,5,6,7,8-hexahydroquinazolin-6- yl)methanesulfonamide with longer retention timeobtained by SFC (column: CHIRALPAK IC-3, mobile phase: carbondioxide/0.05% diethylamine in MeOH)

488.2 165 rac-N-{(3R,6S,7S,9aR)-6-[(3′- fluoro[1,1′-biphenyl]-3-yl)methyl-3-methyl-4- oxooctahydropyrido[2,1- c][1,4]oxazin-7-yl}methanesulfonamide

447.1 166 rac-N-[(5R,6S,8R)-5-[([1,1′- biphenyl]-3-yl)methyl]-8-fluoro-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

470.2 167 rac-N-{(5S,7S,8R)-2-ethyl-5-fluoro-8-[(2-fluoro[1,1′-biphenyl]- 3-yl)methyl]-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-7- yl}methanesulfonamide

473.2 168 N-[(5R,6S)-5-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]-1- fluoromethanesulfonamide

506.2 169 rel-N-[(5R,6S)-4-oxo-5-[(2- phenyl-1,3-thiazol-4-yl)methyl]-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]cyclopropanesulfonamide, which was derived from rel-tert- butyl{(5R,6S)-4-oxo-5-[(2- phenylthiazol-4-yl)methyl]-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6- yl}carbamate withlonger retention time obtained by HPLC (column: CHIRALPAK OD-H, mobilephase: hexane/EtOH)

485.1 170 N-[(5R,6S)-5-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]ethanesulfonamide

502.2 171 1-fluoro-N-[(5R,6S)-5-[(2′- fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

488.1 172 N-[(5R,6S)-5-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]cyclopropanesulfonamide

514.2 173 rac-N-[(5R,6R)-5-[([1,1′- biphenyl]-3-yl)methyl]-7-fluoro-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

470.2 174 N-{(5R,6S)-4-oxo-3-(propan-2- yl)-5-[(2,2′,3′-trifluoro[1,1′-biphenyl]-3-yl)methyl]- 3,4,5,6,7,8-hexahydroquinazolin-6-yl}cyclopropanesulfonamide

532.2 175 N-[(5R,6S)-5-[(3′,5′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]cyclopropanesulfonamide

514.2 176 N-[(5R,6S)-5-[(2-fluoro[1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]cyclopropanesulfonamide

496.2 177 N-[(5R,6S)-5-[(3′,5′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]ethanesulfonamide

502.2 178 rac-N-[(5R,6R)-5-[([1,1′- biphenyl]-3-yl)methyl]-7,7-difluoro-4,8-dioxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]methanesulfonamide

502.2 179 N-[(5RS,6RS)-5-[([1,1′- biphenyl]-3-yl)methyl]-7-fluoro-4,8-dioxo-3-(propan-2-yl)- 3,4,5,6,7,8-hexahydroquinazolin-6-yl]methanesulfonamide

484.1 180 1-fluoro-N-[(5R,6S)-5-[(2- fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamide

514.2 181 N-[(5R,6S)-5-[(2,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]-1- fluorocyclopropane-1- sulfonamide

532.2 182 1-fluoro-N-{(5R,6S)-4-oxo-3- (propan-2-yl)-5-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3- yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin-6- yl}cyclopropane-1-sulfonamide

550.1 183 N-[(5R,6S)-5-[(2,2′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]-1- fluorocyclopropane-1- sulfonamide

532.1 184 1-fluoro-N-{(5R,6S)-4-oxo-3- (propan-2-yl)-5-[(2,2′,3′-trifluoro[1,1′-biphenyl]-3- yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin-6- yl}cyclopropane-1-sulfonamide

550.1 185 rel-N-{5-[([1,1′-biphenyl]-3- yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl}-1- fluorocyclopropane-1-sulfonamide with shorter retention time obtained by HPLC (column:CHIRALPAK IG, mobile phase: hexane/EtOH)

496.2 186 rel-1-fluoro-N-{5-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl}cyclopropane-1-sulfonamide with shorterretention time obtained by HPLC (column: CHIRALPAK IG, mobile phase:hexane/EtOH)

514.2 187 rel-N-[(5R,6S)-5-[(3′,5′- difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]-1- fluorocyclopropane-1- sulfonamide withshorter retention time obtained by HPLC (column: CHIRALPAK IG, mobilephase: hexane/EtOH)

532.1 188 N-[(5R,6S)-5-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]cyclopropanesulfonamide

496.2 189 rel-N-{(7R,8S)-2-ethyl-8-[(2′- fluoro[1,1′-biphenyl]-3-yl)methyl]-1-oxo-1,2,5,6,7,8- hexahydroisoquinolin-7-yl}methanesulfonamide with longer retention time obtained by HPLC(column: CHIRALPAK IC, mobile phase: hexane/EtOH)

455.2 190 rel-1-fluoro-N-{5-[(2′-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl}cyclopropane-1-sulfonamide with longerretention time obtained by HPLC (column: CHIRALPAK AS-H, mobile phase:hexane/EtOH)

514.1 191 rel-N-{5-[(2′,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl}-1- fluorocyclopropane-1- sulfonamide withlonger retention time obtained by HPLC (column: CHIRALPAK AS-H, mobilephase: hexane/EtOH)

532.1 192 N-[(5R,6S)-5-[(2′-fluoro[1,1′- biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]cyclopropanesulfonamide

496.2 193 N-[(5R,6S)-5-[(2′,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]cyclopropanesulfonamide

514.2 194 rel-1-fluoro-N-{4-oxo-5-[(2- phenyl-1,3-thiazol-4-yl)methyl]-3-(propan-2-yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl}cyclopropane-1-sulfonamide with longer retention time obtained byHPLC (column: CHIRALPAK IC, mobile phase: hexane/EtOH)

503.1 195 N-{(5R,6S)-4-oxo-3-(propan-2- yl)-5-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]- 3,4,5,6,7,8-hexahydroquinazolin-6-yl}cyclopropanesulfonamide

532.1 196 1-fluoro-N-{(5R,6S)-4-oxo-3- (propan-2-yl)-5-[(2,2′,3′-trifluoro[1,1′-biphenyl]-3- yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin-6- yl}methanesulfonamide

524.2 197 rac-1-fluoro-N-[(5R,6S)-5-{[3-(2- methylprop-1-en-1-yl)phenyl]methyl}-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]cyclopropane-1-sulfonamide

474.2 198 rac-N-[(5R,6R,7S,8S)-7,8- difluoro-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]methanesulfonamide

506.1 199 1-fluoro-N-{(5R,6S)-4-oxo-3- (propan-2-yl)-5-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3- yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin-6- yl}methanesulfonamide

524.2 200 N-[(5R,6S)-5-[(2′,3′-difluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- (propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6- yl]ethanesulfonamide

502.2 201 rac-N-{(5S,6S)-5-[(3′,5′- difluoro[1,1′-biphenyl]-3-yl)methyl]-2-methyl-3-oxo- 2,3,5,6,7,8-hexahydroimidazo[1,5-a]pyridin-6- yl}methanesulfonamide

448.2 202 rac-N-{(5S,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-2-ethyl-3-oxo-2,3,5,6,7,8- hexahydroimidazo[1,5-a]pyridin- 6-yl}methanesulfonamide

426.3 203 rac-N-[(5S,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-3-oxo-2-(propan-2-yl)-2,3,5,6,7,8- hexahydroimidazo[1,5-a]pyridin-6-yl]methanesulfonamide

440.2 204 rac-N-{(5S,6S)-2-ethyl-5-[(2- fluoro[1,1′-biphenyl]-3-yl)methyl]-3-oxo-2,3,5,6,7,8- hexahydroimidazo[1,5-a]pyridin-6-yl}methanesulfonamide

444.2 205 (2S)-N-{(5SR,6SR)-5-[([1,1′- biphenyl]-3-yl)methyl]-2-methyl-3-oxo-2,3,5,6,7,8- hexahydroimidazo[1,5-a]pyridin-6-yl}oxolane-2-carboxamide

432.3 206 rel-N-[(5R,6R,7R)-7-fluoro-5-[(2- fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2- yl)-3,4,5,6,7,8- hexahydroquinazolin-6-yl]cyclopropanesulfonamide with longer retention time obtained by HPLC(column: CHIRALPAK AS- H, mobile phase: hexane/EtOH)

514.2 207 rac-N-[(5R,6S,8R)-8-fluoro-1- methyl-4-oxo-5-[(2-phenyl-1,3-thiazol-4-yl)methyl]-3-(propan-2- yl)-1,4,5,6,7,8-hexahydrocinnolin-6-yl]methanesulfonamide

491.1 208 rel-N-[(4aR,5S)-4-[([1,1′- biphenyl]-3-yl)methyl]-1-methyl-3-oxo-2-(propan-2-yl)-2,3,4,5,6,7- hexahydro-1H-indazol-5-yl]methanesulfonamide with shorter retention time obtained by SFC(column: CHIRALPAK IB, mobile phase: carbon dioxide/MeOH)

454.2 209 rac-N-{(5S,6S)-2-methyl-3-oxo-5-[(2,3′,5′-trifluoro[1,1′-biphenyl]- 3-yl)methyl]-2,3,5,6,7,8-hexahydroimidazo[1,5-a]pyridin- 6-yl}methanesulfonamide

466.0 210 rac-N-[(4R,5S)-4-[(2,3′- difluoro[1,1′-biphenyl]-3-yl)methyl]-1-methyl-3-oxo-2- (propan-2-yl)-2,3,4,5,6,7-hexahydro-1H-indazol-5- yl]methanesulfonamide

490.0 211 rac-N-{(5R,6S)-5-[([1,1′- biphenyl]-3-yl)methyl]-3-ethyl-1,2-dimethyl-4-oxo-1,4,5,6,7,8- hexahydroquinolin-6-yl}methanesulfonamide

465.0 212 rel-N-{(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- [(~2~H_7_)propan-2-yl]-3,4,5,6,7,8-hexahydroquinazolin- 6-yl}cyclopropanesulfonamide withshorter retention time obtained by SFC (column: CHIRALCEL OJ-H, mobilephase: carbon dioxide/MeOH)

503.2 213 rel-1-fluoro-N-{(5S,6R)-5-[(2- fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3- [(~2~H_7_)propan-2-yl]-3,4,5,6,7,8-hexahydroquinazolin- 6-yl}cyclopropane-1-sulfonamide withlonger retention time obtained by HPLC (column: CHIRALPAK AD, mobilephase: hexane/2-propanol)

521.2 214 rac-N-{(3S,4S)-4-[([1,1′- biphenyl]-4-yl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin- yl}methanesulfonamide

423.0 215 rac-N-{(7S,8S)-8-[([1,1′- biphenyl]-3-yl)methyl]-2-methyl-1-oxo-5,6,7,8-tetrahydro-1H- pyrazolo[1,2-a]pyridazin-7-yl}methanesulfonamide

412.1 216 rac-N-{(3S,4S)-4-[(4- ethylphenyl)methyl]-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H- quinolizin-3- yl}methanesulfonamide

375.1

Experimental Example 1: Obtainment of Cell Stably Expressing HumanOrexin Type 2 Receptor (hOX2R)

To obtain a cell clone stably expressing human orexin type 2 receptor,human orexin type 2 receptor cDNA was inserted into pcDNA3.1(+) plasmidvector (Invitrogen), and a plasmid DNA for expression of human orexintype 2 receptor (pcDNA3.1(+)/hOX2R) was cloned. The plasmid DNA wasintroduced into CHO-dhfr cell by an electroporation method, and humanorexin type 2 receptor expressing clone cells were obtained by limitingdilution method by using G418 drug resistance as a selection marker.

Experimental Example 2: Measurement of Orexin Type 2 Receptor AgonistActivity

CHO cells forcibly expressing human OX2 receptor were seeded in eachwell of 384 well black transparent bottom plate (BD Falcon) at 7,500cells/well, and cultured for one day in a 5% CO₂ incubator at 37° C.After removal of the medium in the cell plate, assay buffer A containinga calcium indicator (HBSS (Thermo Fisher Scientific), 20 mM HEPES(Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg/mL Fluo-4AM (DOJINDO Chemical), 0.08% Pluronic F127 (DOJINDO Chemical), 1.25 mMprobenecid (DOJINDO Chemical)) was added at 30 μL/well. The plate wasstood for 30 min in a 5% CO₂ incubator at 37° C., and further stood atroom temperature for 30 min. A test compound prepared by diluting withassay buffer B (HBSS, 20 mM HEPES, 0.1% BSA) was added at 10 μL/well,and the fluorescence value was measured by FDSSpCELL (HamamatsuPhotonics K.K.) every one sec for 1 min, and thereafter every two secfor 1 min 40 sec. The activity (%) of the test compound was calculatedassuming that variation in the fluorescence value when DMSO was addedinstead of the test compound was 0%, and variation in the fluorescencevalue when orexin A (human) (PEPTIDE INSTITUTE, INC.) was added at thefinal concentration of 10 nM was 100%. The activity of each compound atthe concentration of 3 μM was shown in Table 2. As is clear from theresults, the compound of the present invention was shown to have anagonist activity on human orexin type 2 receptor.

TABLE 2 0X2R agonist Ex. No. activity (3 μM, %) 1 79 8 97 10 101 11 10612 112 13 112 14 107 15 106 16 95 19 122 20 113 21 101 22 106 26 101 2799 28 97 31 100 33 87 34 105 39 89 40 93 43 90 44 96 46 102 47 96 52 9054 97 56 93 58 92 59 86 60 83 61 51 62 92 63 92 64 100 67 105 69 94 7097 71 90 74 91 75 92 78 100 79 102 80 93 81 96 83 100 85 98 87 97 89 10193 101 94 89 96 71 97 82 98 107 99 95 101 98 102 100 103 79 104 89 106103 108 100 117 97 119 105 120 98 124 105 126 103 127 105 129 98 132 104133 72 134 111 135 90 136 89 138 44 140 94 141 103 145 92 146 96 147 100148 104 149 105 150 98 151 107 152 94 154 100 155 104 156 93 157 99 158101 161 101 162 101 163 94 165 97 167 93 169 91 170 87 172 95 173 91 17585 176 93 177 95 179 100 180 94 181 91 182 101 183 95 184 98 185 95 18690 187 94 188 107 191 90 192 101 193 97 194 91 195 94 196 91 197 92 19885 199 90 200 89 201 91 203 86 204 91 205 81 206 96 207 93 208 95 209 74211 82 212 99 213 105 214 52 216 76

Experimental Example 3: Evaluation of Wake-Promoting Effects inCynomolgus Mice

The wake-promoting effects were evaluated by measuring theelectroencephalogram (EEG) and electromyogram (EMG) in cynomolgus mice(C57BL/6Jmice, CLEA Japan Inc., Tokyo, Japan). Under pentobarbitalsodium anesthesia (50 mg/kg, intraperitoneal, Somnopentyl®, KyoritsuSeiyaku, Tokyo, Japan), 11-old male cynomolgus mice were surgicallyimplanted with EEG electrode and EMG electrode. Bilateral EEG leads(Biotex, Kyoto, Japan) were stereotaxically positioned at the parietalarea and secured to the cranium with stainless-steel screws in contactwith the dura. Bilateral EMG leads (Biotex) were implanted into the backcervical muscles. After at least a 1-week recovery period in home cages,the cynomolgus mice were habituated to the recording chamber located inan electrically shielded soundproof room. After habituated, the corticalEEG and EMG signals were recorded using VitalRecorder® (Kissei ComtecCo., Ltd., Nagano, Japan). The signals were automatically scored in 4sec epochs by a sleep scoring system (SleepSign®, Kissei Comtec Co.,Ltd.). Test compound (30 mg/kg, Table 3X-1) dissolved in a mixedsolution containing 10% DMSO, 10% Cremophor EL, 20% PEG400 and 60% H₂O,or vehicle (i.e., a mixed solution containing 10% DMSO, 10% CremophorEL, 20% PEG400 and 60% H₂O) was administered orally (p.o.) to thecynomolgus mice at zeitgeber time 5 in a volume of 10 mL/kg. The EEG andEMG recordings were performed for 2 h after the compound administration.The time spent in wakefulness for 2 h after administration (% of vehicletreatment) was calculated by using SleepSign. The results were shown inTable 3.

TABLE 3 Wakefulness time Test compound (% of vehicle treatment) (30mg/kg, p.o.) (Mean, n = 3) Example 172 201.32 Example 176 204.27 Example180 197.28 Example 195 183.08

As is clear from the results, the test compounds of the presentinvention increased the wakefulness time as compared with the vehicletreatment group in cynomolgus mice. That is, these compounds were shownto be effective for the treatment of narcolepsy.

Formulation Example 1 (Production of Capsule)

1) compound of Example 1 30 mg 2) crystalline cellulose 10 mg 3) lactose19 mg 4) magnesium stearate 1 mg total 60 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Production of Tablet)

1) compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 4)calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000tablets 140 g in total

The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water,vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and1 g of 5), and the mixture is punched by a tableting machine. In thisway, 1000 tablets containing 30 mg of the compound of Example 1 pertablet are obtained.

INDUSTRIAL APPLICABILITY

The compound of the present invention has an orexin type 2 receptoragonist activity, and is useful as an agent for the prophylaxis ortreatment of narcolepsy.

This application is based on patent application No. 2018-232992 filed onDec. 12, 2018 in Japan, the contents of which are encompassed in fullherein.

1. A compound represented by the formula:

wherein R¹ is an optionally substituted C₁₋₆ alkylsulfonyl group, anoptionally substituted mono- or di-C₁₋₆ alkylaminosulfonyl group, anoptionally substituted 3- to 6-membered cyclylsulfonyl group, aformylcarbonyl group, a carboxycarbonyl group, a carbamoylcarbonylgroup, an optionally substituted C₁₋₆ alkyl-carbonyl group, anoptionally substituted C₁₋₆ alkoxy-carbonyl group, an optionallysubstituted mono- or di-C₁₋₆ alkyl-carbamoyl group, an optionallysubstituted C₁₋₆ alkyl-carbonyl-carbonyl group, an optionallysubstituted C₁₋₆ alkoxy-carbonyl-carbonyl group, an optionallysubstituted mono- or di-C₁₋₆ alkyl-carbamoyl-carbonyl group or anoptionally substituted 3- to 6-membered cyclylcarbonyl group; R² and R³are each independently a hydrogen atom, an optionally substituted C₁₋₆alkyl group or a halogen atom; X is an optionally substituted methylenegroup, NR^(a) or an oxygen atom; R^(a) is a hydrogen atom or anoptionally substituted C₁₋₆ alkyl group; Y and Z are each independentlya carbon atom, CH or a nitrogen atom;

is Z—Y or Z═Y; Ring A is an optionally further substituted 5- or6-membered nitrogen-containing non-aromatic heterocycle; L is anoptionally substituted methylene group, an oxygen atom, —O-L¹-, -L¹-O—or -L¹-L²-; L¹ and L² are each independently an optionally substitutedmethylene group; and Ring B is an optionally further substituted 4- to7-membered ring, or a salt thereof.
 2. The compound or salt according toclaim 1, wherein L is an optionally substituted methylene group or anoxygen atom.
 3. The compound or salt according to claim 1, wherein R¹ is(1) an optionally halogenated C₁₋₆ alkylsulfonyl group, (2) a C₃₋₆cycloalkylsulfonyl group optionally substituted by 1 to 3 halogen atoms,(3) a mono- or di-C₁₋₆ alkyl-carbamoyl-carbonyl group, (4) a C₃₋₆cycloalkyl-carbonyl group optionally substituted by 1 to 3 C₁₋₆ alkoxygroups, or (5) a 3- to 6-membered non-aromatic heterocyclylcarbonylgroup; R² is a hydrogen atom or a halogen atom; R³ is a hydrogen atom ora halogen atom; X is (1) a methylene group optionally substituted by 1or 2 substituents selected from a C₁₋₆ alkoxy group and a halogen atom,or (2) a carbonyl group; the partial structure represented by

is a partial structure represented by

Ring A is a 5- or 6-membered nitrogen-containing non-aromaticheterocycle optionally further substituted by 1 to 3 substituentsselected from (a) a halogen atom, (b) a cyano group, (c) a C₁₋₆ alkylgroup (the C₁₋₆ alkyl group is optionally deuterated) optionallysubstituted by 1 to 3 substituents selected from (i) a halogen atom,(ii) a hydroxy group, and (iii) a C₃₋₁₀ cycloalkyl group, (d) a C₁₋₆alkoxy group, (e) a C₃₋₁₀ cycloalkyl group, (f) a C₁₋₆ alkoxy-carbonylgroup, and (g) a mono- or di-C₁₋₆ alkylamino group, and having one oxogroup on the carbon atom adjacent to Z; L is a methylene group; and RingB is a 4- to 7-membered ring further substituted by 1 to 3 substituentsselected from (a) a halogen atom, (b) a C₁₋₆ alkyl group, (c) a C₃₋₁₀cycloalkyl group, (d) a C₆₋₁₄ aryl group (the C₆₋₁₄ aryl group isoptionally fused with a 3- to 8-membered monocyclic non-aromaticheterocycle) optionally substituted by 1 to 3 substituents selected from(i) a halogen atom, (ii) an optionally halogenated C₁₋₆ alkyl group, and(iii) a C₁₋₆ alkoxy group, (e) a 5- to 14-membered aromatic heterocyclicgroup optionally substituted by 1 to 3 C₁-₆ alkyl groups, (f) a 3- to14-membered non-aromatic heterocyclic group optionally substituted by 1to 3 substituents selected from (i) an oxo group, and (ii) a C₁₋₆ alkylgroup, (g) a C₆₋₁₄ aryloxy group, (h) a C₇₋₁₆ aralkyloxy group, and (i)a C₂-₆ alkenyl group.
 4. The compound or salt according to claim 1,wherein R¹ is (1) a C₁₋₆ alkylsulfonyl group, or (2) a C₃₋₆cycloalkylsulfonyl group optionally substituted by 1 to 3 halogen atoms;R² is a hydrogen atom; R³ is a hydrogen atom; X is a methylene group;the partial structure represented by

is a partial structure represented by

Ring A is (1) a dihydropyridine ring optionally substituted by 1 to 3C₁₋₆ alkyl groups, and having one oxo group on the carbon atom adjacentto Z, or (2) a dihydropyrimidine ring optionally substituted by 1 to 3C₁₋₆ alkyl groups, and having one oxo group on the carbon atom adjacentto Z; L is a methylene group; and Ring B is (1) a benzene ring furthersubstituted by 1 or 2 substituents selected from (a) a halogen atom, and(b) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 halogen atoms,or (2) a thiazole ring further substituted by C₆₋₁₄ aryl group(s)optionally substituted by 1 to 3 halogen atoms.
 5. The compound or saltaccording to claim 1, wherein R¹ is a C₃₋₆ cycloalkylsulfonyl groupoptionally substituted by one halogen atom; R² is a hydrogen atom; R³ isa hydrogen atom; X is a methylene group; the partial structurerepresented by

is a partial structure represented by

Ring A is a dihydropyrimidine ring substituted by one C₁₋₆ alkyl group,and having one oxo group on the carbon atom adjacent to Z; L is amethylene group; and Ring B is a benzene ring further substituted by (a)a halogen atom, and (b) a phenyl group optionally substituted by 1 to 3halogen atoms.
 6. The compound of claim 1, which isN-[(5R,6S)-5-[(2-Fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropanesulfonamideor a salt thereof.
 7. The compound of claim 1, which is1-Fluoro-N-[(5R,6S)-5-[(2-fluoro[1,1′-biphenyl]-3-yl)methyl]-4-oxo-3-(propan-2-yl)-3,4,5,6,7,8-hexahydroquinazolin-6-yl]cyclopropane-1-sulfonamideor a salt thereof.
 8. The compound of claim 1, which isN-{(5R,6S)-4-Oxo-3-(propan-2-yl)-5-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]-3,4,5,6,7,8-hexahydroquinazolin-6-yl}cyclopropanesulfonamideor a salt thereof.
 9. A medicament comprising the compound or saltaccording to claim
 1. 10. The medicament according to claim 9, which isan orexin type 2 receptor agonist.
 11. The medicament according to claim9, which is an agent for the prophylaxis or treatment of narcolepsy. 12.The compound or salt according to claim 1 for use in the prophylaxis ortreatment of narcolepsy.
 13. A method for activating an orexin type 2receptor in a mammal, which comprises administering an effective amountof the compound or salt according to claim 1 to the mammal.
 14. A methodfor preventing or treating narcolepsy in a mammal, which comprisesadministering an effective amount of the compound or salt according toclaim 1 to the mammal.
 15. (canceled)